This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for A Study to Explore the Long-Term Safety and Efficacy of Fremanezumab (TEV-48125) for the Prevention of Cluster Headache (NCT03107052), a randomized phase 3 study. The primary outcome is Number of Participants With Adverse Events (AEs).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03107052 |
| Phase | Phase 3 |
| Condition | Cluster Headache |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 275 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Teva Branded Pharmaceutical Products R&D, Inc. |
| Results posted | Yes |
2. Clinical Question
Population
Participants with cluster headache who completed one of the pivotal studies named in the registry record and then enrolled in this study. The safety analysis set included participants who received at least 1 dose of study drug. The registry record describes participants with ECH or CCH in the treatment-arm descriptions, but does not define those abbreviations.
Intervention
Fremanezumab, given in three listed treatment groups: 225 mg monthly, 675/225 mg monthly, and 675 mg quarterly. The arm descriptions indicate that participants’ prior pivotal-study treatment helped determine their subsequent group and regimen.
Comparator
The registry record lists the three fremanezumab groups, but does not report a placebo or untreated comparator for the current study. It also does not report a specific pairwise comparison among the groups.
Primary question
How many participants experienced adverse events from baseline through follow-up, with the primary outcome timeframe extending to Week 68? The registry record also describes a follow-up visit approximately 7.5 months after the last dose to assess safety and other measures.
This is a long-term follow-up study rather than a trial whose posted primary outcome directly compares headache frequency or another efficacy measure. Its primary outcome is the number of participants with adverse events. The record defines an adverse event as an untoward medical occurrence that develops or worsens during the study, whether or not it is considered causally related to study drug. Investigators determined the relationship to treatment.
The central statistical question is therefore descriptive: what adverse events were recorded among participants in each treatment group during the stated observation period? Without a reported comparator analysis, the counts do not establish whether groups differed. The registry record does not report a primary efficacy result or an analysis comparing headache outcomes.
3. Trial Design
The registry record identifies NCT03107052 as a phase 3, randomized, parallel-group study with quadruple masking. Its title describes a multicenter, double-blind, double-dummy study of fremanezumab for cluster headache. Enrollment is listed as 275. The study began on 2017-04-27, had a primary completion date of 2019-06-11, and is marked terminated.
The brief summary describes a 68-week study intended to evaluate long-term safety and efficacy. Participants first completed one of the pivotal studies named in the record, then enrolled in this study. The treatment descriptions distinguish participants by their earlier pivotal-study treatment and by cluster headache type, and list three fremanezumab regimens: 225 mg monthly, 675/225 mg monthly, and 675 mg quarterly. The current-study treatment allocation details beyond the listed groups are not reported in the registry record.
Participants were scheduled for investigational product administration and safety and efficacy assessments at the study center. The record also describes blood and urine collection for pharmacokinetics, immunogenicity, including anti-drug antibodies, and biomarker analyses. A follow-up visit was planned approximately 7.5 months after the last dose to evaluate safety, fremanezumab concentrations, biomarkers, and anti-drug antibodies.
Randomization and masking can reduce some forms of bias, but their presence does not by itself show that treatment groups were comparable in every relevant respect or that an outcome difference was caused by treatment. The registry record does not report the randomization procedure, allocation concealment details, or which groups of people were masked. It also does not report why the study was terminated or how termination affected follow-up and data collection.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Before assignment: Participants were assigned to receive treatments in fremanezumab 225 milligrams (mg) monthly, fremanezumab 675/225 mg monthly, or fremanezumab 675 mg quarterly groups; based on their randomization in the pivotal studies TV48125-CNS-30056 (NCT02945046) and TV48125-CNS-30057 (NCT02964338).
Overall Study
| Stage | Fremanezumab 225 mg Monthly | Fremanezumab 675/225 mg Monthly | Fremanezumab 675 mg Quarterly |
|---|---|---|---|
| STARTED | 145 | 60 | 70 |
| Safety Analysis Set | 144 | 60 | 71 |
| COMPLETED | 26 | 14 | 29 |
| NOT COMPLETED | 119 | 46 | 41 |
Reasons for not completing this period:
| Reason | Fremanezumab 225 mg Monthly | Fremanezumab 675/225 mg Monthly | Fremanezumab 675 mg Quarterly |
|---|---|---|---|
| Adverse Event | 6 | 1 | 2 |
| Withdrawal by Subject | 9 | 5 | 8 |
| Protocol Violation | 6 | 0 | 3 |
| Lost to Follow-up | 4 | 0 | 1 |
| Lack of Efficacy | 23 | 7 | 4 |
| Other than specified | 4 | 2 | 0 |
| Study terminated due to futility | 67 | 31 | 23 |
Analysis population for the primary outcome, as defined in the registry: Safety analysis set included all participants who received at least 1 dose of study drug.
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
Population: ITT analysis set included all participants who were enrolled in this study for long-term safety evaluation, regardless if they received study treatment or not.
| Characteristic | Unit | Fremanezumab 225 mg Monthly | Fremanezumab 675/225 mg Monthly | Fremanezumab 675 mg Quarterly | Total |
|---|---|---|---|---|---|
| Participants analysed | 145 | 60 | 70 | 275 | |
| Age, Continuous | years | 45.2 (SD 12.25) | 46.1 (SD 11.14) | 43.2 (SD 11.40) | 44.9 (SD 11.81) |
| Sex: Female, Male: Female | Participants | 51 | 20 | 25 | 96 |
| Sex: Female, Male: Male | Participants | 94 | 40 | 45 | 179 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 9 | 3 | 2 | 14 |
| Race (NIH/OMB): White | Participants | 136 | 56 | 68 | 260 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 1 | 0 | 1 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Participants With Adverse Events (AEs), measured over Baseline up to follow-up (Week 68).
| Element | Registry entry |
|---|---|
| Result type | Count Of Participants |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary outcome is the number of participants with adverse events, measured from baseline through follow-up, with the stated timeframe extending to Week 68. The record defines an adverse event as an untoward medical occurrence that develops or worsens in severity during the study. An event need not have a causal relationship to study drug to meet that definition; the investigator assessed its relationship to treatment.
The record says that baseline refers to baseline values from the pivotal studies. The safety analysis set includes all participants who received at least 1 dose of study drug. This population is appropriate for describing events observed after exposure, although the registry record does not describe further rules for attributing events to a treatment period or handling participants with incomplete follow-up.
Counting participants with events is a useful safety summary because it indicates how many people were affected, rather than simply how many event reports were recorded. The count does not show event severity, duration, recurrence, or whether several events occurred in the same participant. The record separately identifies serious adverse events and other non-serious adverse events in its adverse-event information.
The endpoint is not itself a measure of headache prevention. Although the study’s stated purpose includes efficacy, the posted primary outcome information concerns adverse events, and a statistical efficacy outcome or efficacy comparison is not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted safety counts are descriptive. For serious adverse events, the registry lists 8 participants among 144 at risk in the 225 mg monthly group, 2 among 60 in the 675/225 mg monthly group, and 1 among 71 in the 675 mg quarterly group. For other non-serious adverse events, it lists 31 among 144, 11 among 60, and 14 among 71, respectively. These are participant counts, not counts of all individual event episodes.
The registry lists zero deaths in each of the three groups. It also names serious adverse-event terms and gives percentages: Cluster headache, 2.1%; Influenza, 1.7%; Rotator cuff syndrome, 1.7%; Acute respiratory failure, 1.7%; Amaurosis fugax, 1.4%; and Carotid artery stenosis, 1.4%. The record does not specify group-specific counts for these listed terms in the information available for this outcome.
These figures describe events among the people at risk in each group. They should not be read as evidence that one regimen is safer or less safe than another: no statistical comparison, adjusted estimate, confidence interval, or hypothesis test is reported. The groups also differ in size, and the posted counts alone do not quantify uncertainty around the group-specific event frequencies.
The study was randomized and masked, but those design features cannot substitute for a reported analysis. A treatment comparison would require a defined contrast and an analysis appropriate to the endpoint and follow-up, along with enough detail to understand how incomplete observation and other design features were handled. Such details are not reported in the registry record.
The record reports a primary outcome focused on safety and describes efficacy assessment as part of the study. It does not report results for a headache efficacy endpoint. Consequently, the posted safety numbers cannot answer whether fremanezumab changed headache outcomes. Nor do the adverse-event counts alone establish that an event was caused by treatment; the record says investigators assessed relatedness, but group-level causality results are not reported.
9. Statistical Methods Explained
The registry record identifies a randomized, parallel-group, quadruple-masked design. It does not report a statistical analysis plan or the specific methods used to produce the posted adverse-event summaries. The explanations below are general statistical context, not claims about analyses performed in this study.
What does a participant count measure?
For a binary safety outcome, each participant is classified according to whether the event occurred during the defined observation period. A count of participants with an event describes how many people met that definition. It is different from a count of event episodes: one participant may experience more than one event, while a participant-level count records that person as affected. The registry labels the primary outcome as a count of participants.
Counts need their denominators to be interpretable. The adverse-event information gives the number at risk in each group along with the number affected. The groups have different numbers at risk, so raw counts alone are not a like-for-like comparison. A formal comparison would ordinarily need to account for the number of people observed and for the endpoint definition. No formal comparison is reported in the registry record.
Why does follow-up matter?
An adverse event can only be observed while relevant information is collected. If follow-up duration varies, participants may have different opportunities for an event to be recorded. The registry describes an endpoint timeframe through Week 68 and a follow-up visit approximately 7.5 months after the last dose. It does not report participant-level follow-up duration, the amount of missing outcome information, or the analysis method for unequal observation time.
In general, time-to-event methods may be useful when the timing of an event and differing follow-up are important. A participant-count summary does not preserve the timing of events. The registry record does not report a time-to-event analysis for this primary outcome, so one should not infer that event timing was incorporated in the posted counts.
What can confidence intervals tell readers?
In general, a confidence interval expresses uncertainty around an estimated quantity under a specified statistical model and procedure. For event counts or group comparisons, an interval can show how imprecisely the underlying event frequency or difference is estimated. It does not, by itself, show that an event was caused by treatment, and its interpretation depends on the method used.
No confidence intervals or inferential comparisons for the posted primary outcome are reported in the registry record. The counts therefore support a description of the observed safety data, but do not quantify statistical uncertainty or establish a difference among groups.
What do randomization and masking contribute?
In general, random allocation is intended to make treatment groups comparable on average with respect to measured and unmeasured factors. Masking can limit the influence of treatment knowledge on participant reporting, clinical management, and outcome assessment. These design features are safeguards, not guarantees: their value depends on implementation, follow-up, and analysis. The registry record states that the study was randomized and quadruple-masked, but does not describe the allocation procedure or identify the roles covered by masking.
How should planning illustrations be understood?
General sample-size planning asks how many participants may be needed to detect a specified effect under assumed statistical conditions. The planning information associated with this study is described as an illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. It is not the trial’s own design justification, and the registry record does not report that justification. A planning illustration is not evidence about the study’s actual statistical power or a result observed in participants. No planning values are reported in the information available for this analysis, so no numerical sample-size conclusion can be drawn.
The record lists no analyses for this outcome and does not provide estimates from an inferential model. The exact model, handling of repeated events, adjustment for baseline factors, and any sensitivity analyses are not reported in the registry record. Statistical concepts can clarify what information a complete analysis might provide, but they cannot fill in these missing study-specific details.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists 12 outcome measures, but does not report a multiplicity plan describing how the study handled the possibility of testing several outcomes or comparisons. In general, testing multiple hypotheses can increase the chance of at least one apparently notable result by chance. Prespecified testing sequences or other adjustments can address that issue, but the methods used in this study are not reported in the registry record. The record lists no analyses for the primary outcome in the posted results.
Missing data are also important in a long-term safety study. Participants may have different amounts of observed follow-up, and some event information may be unavailable. The registry record does not report the extent or pattern of missing data, the reasons for missingness, or a method for handling incomplete outcome information. It also does not report whether analyses used all available observations or applied a particular imputation or censoring rule.
The primary outcome specifies a safety analysis set consisting of participants who received at least 1 dose of study drug. The adverse-event group information gives numbers at risk, but the record does not describe additional analysis populations, exclusions, or the relationship between those denominators and all enrolled participants. Although enrollment is listed as 275, the posted material does not reconcile that figure with the group-specific safety denominators.
Without a multiplicity plan, missing-data details, and a reported statistical analysis, the reader cannot assess how these choices may affect uncertainty or interpretation. The counts remain useful as descriptive safety information, but they do not establish a confirmatory difference among treatment groups.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Fremanezumab 225 mg Monthly | 8 | 144 | 5.6% |
| Fremanezumab 675/225 mg Monthly | 2 | 60 | 3.3% |
| Fremanezumab 675 mg Quarterly | 1 | 71 | 1.4% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Fremanezumab 225 mg Monthly | 0 of 144 |
| Fremanezumab 675/225 mg Monthly | 0 of 60 |
| Fremanezumab 675 mg Quarterly | 0 of 71 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Fremanezumab 225 mg Monthly | 31 of 144 |
| Fremanezumab 675/225 mg Monthly | 11 of 60 |
| Fremanezumab 675 mg Quarterly | 14 of 71 |
Most frequent serious adverse event terms
| Event term | Organ system | Fremanezumab 225 mg Monthly | Fremanezumab 675/225 mg Monthly | Fremanezumab 675 mg Quarterly |
|---|---|---|---|---|
| Cluster headache | Nervous system disorders | 3 of 144 | 0 of 60 | 0 of 71 |
| Acute myocardial infarction | Cardiac disorders | 1 of 144 | 0 of 60 | 0 of 71 |
| Amaurosis fugax | Eye disorders | 0 of 144 | 0 of 60 | 1 of 71 |
| Cholecystitis | Hepatobiliary disorders | 1 of 144 | 0 of 60 | 0 of 71 |
| Cholelithiasis | Hepatobiliary disorders | 1 of 144 | 0 of 60 | 0 of 71 |
| Influenza | Infections and infestations | 0 of 144 | 1 of 60 | 0 of 71 |
| Intentional overdose | Injury, poisoning and procedural complications | 1 of 144 | 0 of 60 | 0 of 71 |
| Lumbar vertebral fracture | Injury, poisoning and procedural complications | 1 of 144 | 0 of 60 | 0 of 71 |
| Road traffic accident | Injury, poisoning and procedural complications | 1 of 144 | 0 of 60 | 0 of 71 |
| Rotator cuff syndrome | Musculoskeletal and connective tissue disorders | 0 of 144 | 1 of 60 | 0 of 71 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Fremanezumab 225 mg Monthly | Fremanezumab 675/225 mg Monthly | Fremanezumab 675 mg Quarterly |
|---|---|---|---|---|
| Nasopharyngitis | Infections and infestations | 16 of 144 | 5 of 60 | 7 of 71 |
| Injection site induration | General disorders | 13 of 144 | 4 of 60 | 5 of 71 |
| Sinusitis | Infections and infestations | 4 of 144 | 3 of 60 | 2 of 71 |
| Nausea | Gastrointestinal disorders | 2 of 144 | 3 of 60 | 0 of 71 |
| Oedema peripheral | General disorders | 0 of 144 | 3 of 60 | 0 of 71 |
Serious events with the highest arm-level rate: cluster headache (2.1%), influenza (1.7%), rotator cuff syndrome (1.7%), acute respiratory failure (1.7%), amaurosis fugax (1.4%).
The serious adverse-event figures count participants with at least one serious adverse event in each group. The registry lists 8 among 144 at risk for 225 mg monthly, 2 among 60 for 675/225 mg monthly, and 1 among 71 for 675 mg quarterly. These are not counts of every serious event episode. A participant with multiple serious events may still contribute as one participant to a participant-level count.
The record defines serious events to include death, a life-threatening event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent those outcomes. It says summaries of other non-serious events and all serious events, regardless of causality, are located in the reported adverse-event information.
Zero deaths are listed for each group. That is a count in this study record, not proof that the risk of death is absent. The listed serious-event terms include Cluster headache, Influenza, Rotator cuff syndrome, Acute respiratory failure, Amaurosis fugax, and Carotid artery stenosis, with percentages reported for those terms. The record does not provide a group-by-group breakdown for these terms in the information.
Neither seriousness nor occurrence establishes treatment causation. The record says investigators assessed relatedness, but does not report a causal comparison among groups. The counts should therefore be read as observed safety information, not as evidence of a treatment effect.
12. What the Result Does, and Does Not, Mean
The posted results show that serious and other non-serious adverse events were recorded among participants in all three listed fremanezumab groups. They also show zero deaths in each group. These findings describe the safety observations recorded for this study’s participants over its stated observation period; they do not, on their own, establish a difference between regimens.
A count of participants with an adverse event is not a complete account of event burden. It does not show when an event occurred, how long it lasted, whether it recurred, or how severe a non-serious event was. The serious-event definition includes several clinically consequential categories, but the counts alone do not convey the circumstances of each event. The record lists some serious-event terms and percentages, but does not provide a complete group-specific account in the information used for this statistical interpretation.
The study title and brief summary refer to long-term safety and efficacy, but the primary outcome described in the registry is the number of participants with adverse events. A headache efficacy endpoint and its results are not reported in the registry record. Therefore, these safety data do not answer whether headache outcomes changed during treatment.
The study’s randomized and masked design is relevant context, but the posted material does not include an inferential analysis or a direct comparator result. There are no reported estimates or confidence intervals to show the precision of a treatment contrast. Differences in observed counts should not be interpreted as evidence of a treatment effect without such an analysis and an understanding of follow-up and missing information.
The registry marks the study terminated. It does not report the reason for termination or the effect, if any, on participant follow-up. The results are best understood as descriptive information from the recorded safety population, with important limits on causal and comparative conclusions.
13. Why This Trial Matters Statistically
This study illustrates a common distinction in clinical-trial interpretation: a trial may be designed to examine several aspects of treatment, while the posted primary outcome addresses only one of them. Here, the study summary refers to long-term safety and efficacy, but the primary outcome is a participant count for adverse events. Keeping that endpoint separate from efficacy prevents safety observations from being mistaken for evidence about headache prevention.
The record also highlights why denominators matter. The serious-event counts are reported alongside the number at risk in each group, and the group sizes are not the same. Reporting both allows readers to understand the scale of the observed data, while the absence of a statistical comparison limits conclusions about relative differences. A descriptive count is useful, but it does not provide the same information as an estimate with uncertainty.
Long-term follow-up raises further statistical questions. Observation may vary between participants, and interpretation can depend on when events occur, how missing information is handled, and how treatment exposure is defined. The registry describes an extended study period and a follow-up visit after the last dose, but does not report the analysis details needed to evaluate those issues.
Finally, randomized and masked design features are important but do not replace transparent reporting of analysis methods and results. The absence of a posted inferential comparison means the safety counts can be read as observations, not as proof of a group difference. This distinction is central to responsible interpretation of registry results.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
The registry record gives limited information about how the study was conducted and analyzed. It identifies randomization, parallel groups, and quadruple masking, but does not describe the randomization procedure, allocation concealment, or which participants and study personnel were masked. It marks the study terminated without reporting why it ended or how termination affected enrollment, treatment, or follow-up.
The listed treatment groups have different numbers at risk, and the record does not reconcile those denominators with the enrollment of 275. It also does not report participant-level follow-up duration, how many participants completed follow-up, or whether time under observation differed among groups. These omissions limit interpretation of counts accumulated over an extended observation period.
The record does not report a statistical analysis plan, inferential comparisons, confidence intervals, adjustment for baseline characteristics, or sensitivity analyses for the primary outcome. The extent and handling of missing data are not reported in the registry record. Details about recurrent events, event timing, and the application of treatment-relatedness assessments are also not reported.
Although efficacy assessment is part of the study summary, the registry record does not report a primary efficacy measure or efficacy result in the information available for this analysis. The posted safety counts cannot substitute for such results. The record also does not report a specific current-study placebo or untreated comparator, so the listed groups do not provide a clearly stated contrast against no fremanezumab treatment in the posted information.
These limits do not invalidate the reported counts; they define what can be concluded from them. The counts describe recorded adverse events in the stated safety population, while comparative, causal, and efficacy interpretations remain unsupported by the reported details.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study to Explore the Long-Term Safety and Efficacy of Fremanezumab (TEV-48125) for the Prevention of Cluster Headache — NCT03107052.
- Registry record last updated 2021-11-09; status last verified 2021-11.
- Results first posted 2020-05-06.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
Continue through the Clinical Biostats statistical pathway
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
18. Record Summary
NCT03107052 is a phase 3 randomized, parallel-group, quadruple-masked study of fremanezumab for cluster headache. Enrollment is listed as 275, and the study is marked terminated. The brief summary describes a 68-week study enrolling participants who completed named pivotal studies, with a follow-up visit approximately 7.5 months after the last dose.
The primary outcome is the number of participants with adverse events from baseline through follow-up, with the timeframe stated as through Week 68. The safety analysis set includes participants who received at least 1 dose. Three treatment groups are listed: 225 mg monthly, 675/225 mg monthly, and 675 mg quarterly. The registry reports serious and other non-serious adverse-event participant counts, along with zero deaths in each group.
The registry record does not report a statistical comparison for the primary outcome, an efficacy result, or the details of the analysis plan, missing-data handling, or reason for termination. The posted counts are descriptive and do not establish comparative safety or efficacy.