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Trial registered on ANZCTR


Registration number
ACTRN12617001323314
Ethics application status
Approved
Date submitted
6/09/2017
Date registered
15/09/2017
Date last updated
13/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Pilot phase for the Tension-type HeadAche Prevention Project (HAPPy Too) to investigate in a double-blind, randomised trial whether treatment with low-dose blood pressure (BP) lowering therapy on top of standard care will reduce tension-type headache compared to placebo and standard care.
Scientific title
An investigator initiated, multicentre, randomised, double blind placebo controlled study to assess the effectiveness and tolerability of low-dose combination blood pressure-lowering therapy in patients with tension-type headache and borderline elevation of blood pressure - pilot
Secondary ID [1] 292710 0
None
Universal Trial Number (UTN)
Trial acronym
HAPPy Too
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Tension-type Headache 304469 0
Condition category
Condition code
Neurological 303806 303806 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The HAPPy Too trial is a double-blind randomised controlled trial in participants with frequent episodic tension-type headache (TTH). The duration of the trial is 16 weeks in total (12 weeks of treatment + 4 weeks of observation) with an additional 4-week screening period prior to randomisation.
The 4-week screening period will record number of headache days in that month and laboratory test results to confirm eligibility to receive study treatment. All eligible participants will be randomised and followed for a period of 16 weeks. The treatment period will be for 12 weeks. Unblinding will be avoided by using a uniform medication procedure for all groups. Randomised participants who deviate from the protocol/ and or discontinue allocated BP intervention will still be followed up to 16 weeks as their data will be analysed on the ‘intention to treat’ principle. The 13 and 16 week follow ups will assess for rebound headache and hypertension.
During the 12-week treatment period, participants will be randomised to one of two arms: low-dose combination of telmisartan (20mg), amlodipine (2.5mg) and indapamide (1.25mg) OR placebo. Participants will take one capsule orally, daily. The capsule will either be a low-dose combination (telmisartan + amlodipine + indapamide) or placebo.
To maximise participant’s adherence to the study medications the following processes will be implemented:
• Participant education during all visits on the importance of taking study medication, including timing, storage and what to do in the event of a missed dose
• Participants will be instructed to return unused capsules at visit 5, week 12, and returned capsules will be counted by the study team.
• Reminder text messages to commence study treatment after randomisation
• Participants will be encouraged to contact a member of the study team if for any reason they are unable to continue their study medication or have missed multiple doses and are unsure whether to continue.
Intervention code [1] 298952 0
Treatment: Drugs
Comparator / control treatment
Placebo - commonly used excipients (to be determined) received via blinded study capsules
Control group
Placebo

Outcomes
Primary outcome [1] 303168 0
The change from baseline in mean monthly TTH days at 12 weeks.
Timepoint [1] 303168 0
Headache diary to be completed by participant; reviewed every 4 weeks, patient follow up: 12 weeks
Secondary outcome [1] 338093 0
The change from baseline in mean monthly hours with TTH
Timepoint [1] 338093 0
Headache diary to be completed by participant; reviewed every 4 weeks, patient follow up: 12 weeks
Secondary outcome [2] 338094 0
Proportion of subjects with at least a 50% reduction from baseline in monthly TTH days
Timepoint [2] 338094 0
Headache diary to be completed by participant; reviewed every 4 weeks, patient follow up: 12 weeks
Secondary outcome [3] 338095 0
Change from baseline in monthly TTH medication treatment days
(Medication treatment day is defined as any day in which the patient takes medication other than study medication to treat their TTH.)
Timepoint [3] 338095 0
Headache diary to be completed by participant; reviewed every 4 weeks, patient follow up: 12 weeks
Secondary outcome [4] 338096 0
Change from baseline in monthly lost productive work days due to TTH
Timepoint [4] 338096 0
Headache diary to be completed by participant; reviewed every 4 weeks, patient follow up: 12 weeks
Secondary outcome [5] 338097 0
Change from baseline in the number of reduced productivity work hours per month
Timepoint [5] 338097 0
Headache diary to be completed by participant; reviewed every 4 weeks, patient follow up: 12 weeks
Secondary outcome [6] 338098 0
Change from baseline in health-related quality of life (HRQoL) - assessed through the use of Headache Impact Test-6 (HIT-6)
Timepoint [6] 338098 0
HRQoL will be assessed through the use of Headache Impact Test-6 at Baseline (0 weeks), 12 and 16 weeks
Secondary outcome [7] 338099 0
Change in DBP and SBP
Timepoint [7] 338099 0
Blood pressure (DBP and SBP) will be recorded at screening (-4 weeks), baseline (0 weeks), 4, 8, 12 and 16 weeks
Secondary outcome [8] 338100 0
Tolerability - Difference between groups in potentially-related side-effects (dizziness, blurred vision, syncope/ collapse/ fall, ankle oedema, skin rash, itching, gout, hyperkalaemia, hypokalaemia, hyponatraemia, rebound hypertension)
Timepoint [8] 338100 0
Reviewed every 4 weeks, patient follow up: 12 weeks.
Participants will be asked (self-reported) if they have experienced any of the potentially-related side effects at all visits. These adverse events of special interest (AESIs) will be monitored and recorded as new or ongoing and reported to the CCC regardless of seriousness or severity
Secondary outcome [9] 338101 0
Safety: Percentage with any severe adverse event (SAE)
Self reported by participants during follow up visits.
An SAE is defined as any untoward medical occurrence that at any dose:
• Results in death
• Is life threatening in the opinion of the attending clinician (i.e. The patient was at risk of death at the time of the event; it does not refer to an event that might hypothetically have caused death had it been more severe)
• Requires inpatient hospitalisation or prolongation of existing hospitalisation (any hospitalisation that was planned prior to randomisation will not meet sae criteria. Any hospitalisation that is planned post-randomisation will meet the SAE criteria)
• Results in persistent or significant disability or incapacity
• Results in congenital anomaly or birth defect (note that the females in the study population are likely to be post-menopausal)
• Is an important medical event in the opinion of the attending clinician that is not immediately life-threatening and does not result in death or hospitalisation but which may jeopardise the patient or may require intervention to prevent one of the other outcomes listed above
Timepoint [9] 338101 0
An adverse event that meets the above categories between when the informed consent form is signed and the 1 month post study visit at week 16 will be reported as an SAE. All SAEs are required to be reported to TGI within 24 hours of the study team first becoming aware of the event.
Secondary outcome [10] 338102 0
Medication Adherence: Self-reported measures - participants will inform study personnel if they have missed any doses or misplaced any capsules. Participants will be instructed to return unused capsules at each follow up visit (visit 3-5), and returned capsules will be counted by the study team.
Timepoint [10] 338102 0
Reviewed every 4 weeks, patient follow up: 12 weeks
Secondary outcome [11] 338660 0
Tolerability - Difference between groups in participant withdrawals from treatment
Timepoint [11] 338660 0
Reviewed every 4 weeks, patient follow up: 12 weeks

Eligibility
Key inclusion criteria
• Frequent episodic TTH according to the diagnostic criteria of the IHS
• 2-14 days per month with headache averaged over past 3 months (90-days), as self-reported by subject
• Headache must have been present for >=1 year prior to enrollment in the study.
• Onset of symptoms must have occurred before the age of 50 years
• Adults between 18 and 65 years
• Office SBP >=130mmHg and/or DBP >=80 mmHg
• No definite contraindications to any of the study medications at the doses used in this trial. (Subjects can be taking other preventive and therapeutic medications as long as they do not contraindicate study medication. Patients will not be eligible if they are taking medications from the same class as the study treatments)
• Is medically stable as determined by the Study Investigator
• If the patient has concomitant migraine attacks, he/she must be able to differentiate between TTH and migraine. The frequency of migraine attacks must not exceed one attack per month during the preceding year.
• Is able to take oral medication, adhere to the medication regimens, and perform study procedures over the study duration.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Contraindication to any of telmisartan, amlodipine or indapamide
• Office SBP >=140mmHg and/or DBP >=90 mmHg and high CV risk
• Concomitantly taking an angiotensin II receptor blocker (ARB), angiotensin-converting enzyme inhibitor (ACE-I), calcium channel blocker (CCB), or diuretic or other medications that may adversely affect potassium, sodium or creatinine.
• Definite indication to any one or more of the study medications in accordance with the National Heart Foundation of Australia (NHFA) Guidelines for Diagnosis and Management of Hypertension in Adults and indications per product information sheets
• Subject has history of cluster headaches
• Medication overuse headaches according to IHS criteria
• Female patients who are pregnant, nursing, or those not using adequate birth control, if capable of bearing children.
• Chronic medical illnesses (e.g. lupus) that could potentially affect frequency of headache as determined by the Study Investigator
• Alcohol or substance abuse within the last year
• Any concurrent medical or psychiatric condition which, in the investigator's judgment, may interfere with study conduct or which contraindicates participation
• Clinically significant abnormal creatinine or electrolytes on screening as assessed by Study Investigator
• Inability to provide informed consent.
• Participation in an interventional medical investigation or clinical trial currently or within the past three months. Subjects in observational, natural history and/or epidemiological studies not involving an intervention are eligible.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The randomisation allocation will be blinded to all participants and study team members except the primary study statistician and the manufacturer of the investigational products. All individual medications will be over-encapsulated and concealed by identical packaging, labelling and administration scheduling.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
12/03/2018
Actual
12/04/2018
Date of last participant enrolment
Anticipated
Actual
14/06/2018
Date of last data collection
Anticipated
4/09/2018
Actual
Sample size
Target
120
Accrual to date
Final
10
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment postcode(s) [1] 21942 0
4118 - Browns Plains
Recruitment postcode(s) [2] 21943 0
2100 - Brookvale
Recruitment postcode(s) [3] 21944 0
2168 - Hinchinbrook

Funding & Sponsors
Funding source category [1] 297353 0
Other
Name [1] 297353 0
The George Institute for Global Health
Country [1] 297353 0
Australia
Primary sponsor type
Other
Name
The George Institute for Global Health
Address
Level 10, King George V Building
Missenden Road
Camperdown, NSW 2050
Country
Australia
Secondary sponsor category [1] 296328 0
None
Name [1] 296328 0
Address [1] 296328 0
Country [1] 296328 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298449 0
Sydney Local Health District Ethics Review Committee (Royal Prince Alfred Hospital (RPAH) Zone)
Ethics committee address [1] 298449 0
Ethics committee country [1] 298449 0
Australia
Date submitted for ethics approval [1] 298449 0
10/04/2017
Approval date [1] 298449 0
05/07/2017
Ethics approval number [1] 298449 0
17/RPAH/161
Ethics committee name [2] 299831 0
Bellberry Human Research Ethics Committee
Ethics committee address [2] 299831 0
Ethics committee country [2] 299831 0
Australia
Date submitted for ethics approval [2] 299831 0
Approval date [2] 299831 0
15/02/2018
Ethics approval number [2] 299831 0
2017-10-803-AA

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77130 0
Prof Anthony Rodgers
Address 77130 0
The George Institute for Global Health, Australia
Level 10, King George V Building, 83-117 Missenden Rd,
Camperdown NSW, 2050
Country 77130 0
Australia
Phone 77130 0
+61 2 8052 4375
Fax 77130 0
Email 77130 0
arodgers@georgeinstitute.org
Contact person for public queries
Name 77131 0
Ruth Freed
Address 77131 0
The George Institute for Global Health, Australia
Level 10, King George V Building, 83-117 Missenden Rd,
Camperdown NSW, 2050
Country 77131 0
Australia
Phone 77131 0
+61 2 8052 4522
Fax 77131 0
Email 77131 0
rfreed@georgeinstitute.org.au
Contact person for scientific queries
Name 77132 0
Cheryl Carcel
Address 77132 0
The George Institute for Global Health, Australia
Level 10, King George V Building, 83-117 Missenden Rd,
Camperdown NSW, 2050
Country 77132 0
Australia
Phone 77132 0
+61 2 8052 4508
Fax 77132 0
Email 77132 0
ccarcel@georgeinstitute.org.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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