Safety and efficacy of botulinum toxin A in patients with posttraumatic headache: a double-blind, randomized, placebo-controlled, parallel-group trial and investigation of neuro-inflammatory biomarkers as predictors of efficacy.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rigshospitalet

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

10 Jan 2025 → ongoing

Decision date (initial)

2024-10-03

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To investigate if botulinum toxin type A (BTX-A) is safe and more effective than placebo to lower the number of moderate-to-severe headache days in the evaluation period (weeks 5 to 8) compared to baseline (weeks -4 to -1)

Secondary objectives 5

1. To investigate the degree of change in inflammatory biomarkers in plasma and tears in responders versus non-responders in the BTX-A and placebo groups.
2. To investigate the proportion of subjects reaching a ≥50% or a ≥75% reduction in the number of days with moderate-to-severe headache during the evaluation period (weeks 5 to 8) compared with baseline (weeks -4 to -1), respectively.
3. To evaluate the change from baseline period (weeks -4 to -1) to evaluation period (weeks 5 to 8) in various patient reported outcome measures (PROMs) at week 8 in the BTX-A group versus the placebo group.
4. To evaluate the effectiveness of blinding
5. To evaluate tolerability and safety by: a) Evaluating the proportion of dropouts caused by increased intake of post-traumatic headache (PTH) medication or use of prohibited rescue medication in the BTX-A group compared to the placebo group, or: b) Evaluating the proportion of subjects with side effects registered in the evaluation period (weeks 5 to 8) in the BTX-A group compared to the placebo group.

Conditions and MedDRA coding

Persistent post-traumatic headache

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. A diagnosis of persistent PTH according to criteria 5.2.2 Persistent headache attributed to mild traumatic injury to the head according to The International Classification of Headache Disorders 3rd edition.
2. Age between 18 and 80 years.
3. Subjects must have headache at least 15 days per month during the last 4 weeks to enter the baseline phase.
4. During baseline phase subjects must experience moderate-to-severe headache at least 8 days and headache at least 15 days to enter the treatment phase (to be randomized).
5. Fluency in Danish.

Exclusion criteria 17

1. More than two incidences of traumatic brain injuries.
2. Severe cardiovascular and cerebrovascular disease such as ischemic heart disease, myocardial infarction or previous stroke or transient ischemic attack, major CVD interventions during the last three months.
3. Expected poor compliance, i.e., considered unlikely to be able to complete all protocol required study visits or procedures, and/or to comply with all required study procedures to the best of the subject’s and investigator’s knowledge.
4. Ongoing and unstable severe psychiatric disease.
5. Anamnestic or clinical symptoms of any kind that are deemed relevant for study participation by the physician who examines the patient.
6. A history of migraine or tension-type headache more than 5 days per month before the TBI.
7. Medication-overuse headache according to the according to The International Classification of Headache Disorders 3rd edition.
8. A history of moderate-to-severe TBI, whiplash injury, or craniotomy.
9. Change of preventive PTH treatment or treatment dose within two months prior to the baseline visit (see protocol Section 6.4 for a full list of these medications).
10. Previous treatment with injections of BTX-A in the head or face.
11. Female subjects either pregnant, breastfeeding or with planned conception within the study period.
12. Female subject of childbearing potential who is unwilling to use an acceptable method of effective contraception during the study. Acceptable methods of effective birth control include not having intercourse (true abstinence, when this is in line with the preferred and usual lifestyle of the subject), hormonal birth control methods (pills, shots/injections, implants, or patches), intrauterine devices, surgical contraceptive methods (vasectomy with medical assessment of the surgical success of this procedure or bilateral tubal ligation).
13. Known allergy to any component of BTX-A.
14. Infection at the proposed injection site.
15. Known severe neuromuscular disorders or any degree of disorder affecting the neuromuscular transmission.
16. Known comprised respiratory function.
17. Member of investigational site staff or relative of the investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The proportion of responders in BTX-A and placebo group during the evaluation period (weeks 5 to 8) compared with baseline (weeks -4 to -1). A subject who meets the following criterion will be classified as a responder: Has a reduction of ≥ 30% in number of days having moderate or severe headache

Secondary endpoints 8

1. The degree of change in inflammatory biomarkers (See protocol Section 7.2.14 for the full list) in plasma and tears in responders versus non-responders in BTX-A and placebo group.
2. The proportion of responders in BTX-A and placebo group during the evaluation period (weeks 9 to 12) compared with baseline (weeks -4 to -1). proportion of subjects reaching ≥50% reduction in number of days with moderate-to-severe headache during the evaluation period (weeks 5 to 8) compared with baseline (weeks -4 to -1).
3. The proportion of subjects reaching ≥50% reduction in number of days with moderate-to-severe headache during the evaluation period (weeks 5 to 8) compared with baseline (weeks -4 to -1).
4. The proportion of subjects reaching ≥75% reduction in number of days with moderate-to-severe headache during the evaluation period (weeks 5 to 8) compared with baseline (weeks -4 to -1).
5. Proportion of subjects with a PGI-C scale response of “much improved” or “very much improved” at week 8 in BTX-A group and placebo group.
6. Change from baseline to week 5 in the HIT-6, RPQ, HADS & ISI score in BTX-A and placebo group.
7. Proportion of dropouts caused by increased intake of PTH medication or use of prohibited rescue medication in BTX-A group compared to the placebo group.
8. Proportion of subjects with side effects registered in weeks 2 to 5 during treatment with BTX-A compared with placebo.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rigshospitalet

Sponsor organisation

Rigshospitalet

Address

Valdemar Hansens Vej 1-23

City

Glostrup

Postcode

2600

Country

Denmark

Scientific contact point

Organisation

Rigshospitalet

Contact name

Department of Neurology, Danish Headache Center

Public contact point

Organisation

Rigshospitalet

Contact name

Department of Neurology, Danish Headache Center

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications