Mild Haemophilia A Without InhibitorPhase 4NCT03136003
DDAVP vs. Exercise in Patients With Mild Hemophilia A
A Phase 4 study testing DDAVP and Exercise in people with Mild Haemophilia A Without Inhibitor, run by The Hospital for Sick Children at 2 sites in Canada.
Trial summary
Individuals with mild hemophilia A (MHA) bleed infrequently but can in the setting of trauma which often is when participating in sports/exercise. Although both exercise and DDAVP (desmopressin) can raise Factor 8/Von Willebrand Factor (FVIII/VWF levels), it is not clear whether the pathophysiological mechanism is the… Read more about this study
- Who is it for?
- Ages 13 to 21 years, men only
- Conditions the study is for
- Mild Haemophilia A Without Inhibitor
- What is being tested?
- DDAVP and Exercise
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 2 sitesCanada
- Study dates
- 4 Jul 2017to Aug 2018
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 13 to 21 years
- Men only
- No healthy volunteers
- Child, Adult
Who may be able to join
- Patients ≥13 years of age and ≤21 years of age with Mild Hemophilia A (MHA), with a historical baseline FVIII:C level of ≥5% to ≤40% followed at either the Hospital for Sick Children or St. Michael's Hospital (Toronto).
- Patients ≥13 years of age and ≤21 years of age with genetically confirmed Mild Hemophilia A (MHA), with FVIII:C level of ≥5% to ≤50% followed at either the Hospital for Sick Children or St. Michael's Hospital (Toronto).
Who cannot join
- A currently circulating or history of a previous inhibitor ( ≥0.5 BU) within the past 5 years. As inhibitor development in MHA is rare, it is not expected that any patient will be excluded for this reason.
- Any FVIII infusion or DDAVP use in the preceding week. This is to avoid an residual FVIII still being present in a patient who has taken an extended half-life FVIII.
- Co-existence of a congenital bleeding disorder other than MHA (e.g. VWD).
- Prior history of coronary artery disease or pulmonary disease, severe arthropathy interfering with ability to exercise.
- Patients on beta-blockers, anti-platelet agents or regular non-steroidal anti-inflammatory medications (e.g. Celebrex).
- Patients with an active infectious or inflammatory condition. This includes HIV, active hepatitis B or C as reflected in elevated AST, ALT, RNA positivity for hepatitis B or C.
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- Patients who are active (defined as smoking daily) smokers (cigarettes, marijuana). This exclusion is put into place as we do not know if daily smoking will impact on the hemostatic response to either exercise or DDAVP.
- Patients with limited exercise tolerance for any reason.
- Patients with a history of a recent bleed (in preceding 2 weeks) in any location, or a joint/muscle bleed in the lower limbs in the preceding 4 weeks.
- Patients who for medical reasons should not receive DDAVP [those with renal or CNS disease (e.g. brain tumor)] or have previously experienced adverse events with DDAVP (e.g. hypotensive event; seizure).
Trial locations and contacts
2 sites in 1 country.
Canada2 sites, 2 recruiting
- Not yet recruiting
St. Michael's Hospital
Toronto, Ontario, M5B 1W8
Michelle Sholzberg
Michelle Sholzberg
- Recruiting
The Hospital for Sick Children
Toronto, Ontario, M5G1X8
Manuel Carcao
Patrick Ng
About this study
Official title: DDAVP vs Exercise in Patients With Mild Hemophilia A - Which is Better and do They Work Synergistically in Improving Hemostasis?
Individuals with mild hemophilia A (MHA) bleed infrequently but can in the setting of trauma which often is when participating in sports/exercise. Although both exercise and DDAVP (desmopressin) can raise Factor 8/Von Willebrand Factor (FVIII/VWF levels), it is not clear whether the pathophysiological mechanism is the same. Consequently it is not known if DDAVP and exercise would have additive effects in raising FVIII:C and VWF levels or if one would one negate the effect of the other. The aim of this 2 center (Sickkids and Columbus, Ohio), prospective, cross-over design study is to compare the impact of exercise vs. DDAVP on hemostasis in patients with MHA and also to investigate the impact of sequentially administering these interventions on their hemostatic indices.
Read the detailed description
Persons with mild hemophilia A (MHA) (defined as having a FVIII level of >5% to ≈40%) bleed infrequently but can in the setting of trauma which can often is in the context of participating in sports/exercise. FVIII levels temporarily rise with stress, exercise and with DDAVP (1-desamino-8-D-arginine vasopressin, desmopressin). In the case of DDAVP, the Hospital for Sick Children (SickKids) Hemophilia Team and others have shown that FVIII and VWF levels rise by 2-4 fold with DDAVP. Consequently many persons with MHA in an attempt to reduce their risk of bleeding take intranasal (IN) DDAVP prior to sports activities/exercise. IN DDAVP is reasonably expensive ($300/bottle of Octostim® in Canada and $700/bottle of Stimate® in USA), requires fluid restriction, and may be associated with nausea, vomiting, seizures and tachyphylaxis.
Recently, our group completed a pilot/feasibility study to evaluate the impact of a prescribed, moderate intensity aerobic exercise regimen on hemostatic indices in 30 children with hemophilia A [HA] or B [HB] (all severities) and documented a significant improvement in multiple coagulation parameters (platelet count, FVIII:C and von Willebrand factor [VWF]) with exercise. This improvement was particularly pronounced in 13 post-adolescent males with mild-moderate HA. In this sub-cohort, we noted a mean 2.3 fold increase in FVIII:C immediately after exercise, which remained significantly elevated at 1.9 fold,1 hour after completion of exercise
These changes in hemostatic variables associated with aerobic exercise may be protective against bleeding, and may negate the need to administer IN DDAVP immediately prior to sports participation.
Although both exercise and DDAVP can raise FVIII/VWF levels, it is not clear whether the pathophysiological mechanism in which they do this is the same. Consequently it is not known if DDAVP and exercise would augment each other's effects in raising FVIII:C and VWF levels or if one would one negate the effect of the other. Herein, we propose a prospective, interventional study of exercise vs IN DDAVP in 40-50 post adolescent (13-21 yr) males with MHA to compare their impact on hemostasis and also to investigate the impact of sequentially administering these interventions on hemostatic indices.
- Conditions
- Mild Haemophilia A Without Inhibitor
- Being tested
- DDAVP, Exercise
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DDAVPDrug
Also called IN DDAVP, Octostim
The participant will take either 1 or 2 nasal sprays of IN DDAVP (known as Octostim® in Canada). After receiving IN DDAVP, the participant will rest for 30 minutes.
ExerciseBehavioural
The participant will exercise on a stationary cycle-ergometer using the previously-validated, progressively-incremental Godfrey protocol. Per the Godfrey protocol, the participant starts cycling on the calibrated cycle-ergometer with an initial exercise load dependent on their height. The workload is increased every minute in standard increments also based on the participant's height. All participants will exercise until they complete 3-minutes of cycling at 85% of their maximum predicted heart rate or exhaustion (whichever is first). Upon completion of planned exercise, work load is decreased to zero watts and participants will continue cycling at this cool-down rate for an additional 3-minutes, before getting off the ergometer.
| Study group | Role | What they receive |
|---|---|---|
| Arm A: DDAVP followed by exercise | Experimental | Intervention #1: DDAVP. The participant will take either 1 or 2 nasal sprays of IN DDAVP. For patients weighing <50 kg: 150 ug (i.e. 1 spray into one nostril) and patients weighing ≥50 kg: 300 ug (i.e. 2 sprays - one into each nostril).
Intervention #2: Exercise Receives: Drug: DDAVP; Behavioral: Exercise |
| Arm B: DDAVP alone | Active comparator | Intervention #1: DDAVP. The participant will take either 1 or 2 nasal sprays of IN DDAVP. For patients weighing <50 kg: 150 ug (i.e. 1 spray into one nostril) and patients weighing ≥50 kg: 300 ug (i.e. 2 sprays - one into each nostril).
Intervention #2: no further intervention (rest) Receives: Drug: DDAVP |
| Arm C: Exercise alone | Experimental | Intervention #1: Exercise
Intervention #2: no further intervention (rest) Receives: Behavioral: Exercise |
| ARM D: Exercise followed by DDAVP | Experimental | Intervention #1: Exercise
Intervention #2: DDAVP. The participant will take either 1 or 2 nasal sprays of IN DDAVP. For patients weighing <50 kg: 150 ug (i.e. 1 spray into one nostril) and patients weighing ≥50 kg: 300 ug (i.e. 2 sprays - one into each nostril). Receives: Drug: DDAVP; Behavioral: Exercise |
What is being measured
The primary outcome is the main question the study is designed to answer.
Factor 8 level after exercise
To compare the increase in Factor 8 levels (FVIII:C) (measured as absolute and fold increase) associated with moderate intensity aerobic exercise (approximately 15 minutes of gradually increasing aerobic exercise culminating in 3-minutes of exercise at 85% of the predicted maximum heart rate) vs. IN DDAVP in post-adolescent males with MHA.
Measured: Baseline, 30 min post intervention #1, 30 min post intervention#2 and 90 minute post intervention#2
Secondary outcomes (2)
Factor 8 level after sequential administration of exercise followed by IN DDAVP (or vice versa)
To determine the absolute and fold increase in Factor 8 levels (FVIII:C) associated with the sequential administration of exercise followed by IN DDAVP (or vice versa).
Measured: Baseline, 30 min post intervention #1, 30 min post intervention#2 and 90 minute post intervention#2
Associations between baseline physical activity scores and Factor 8 levels after exercise
To explore the impact of baseline physical activity (measured using the International Physical Activity Questionnaire [IPAQ]-short form) on exercise induced increase in Factor 8 levels (FVIII:C).
Measured: Baseline, 30 min post intervention #1, 30 min post intervention#2 and 90 minute post intervention#2
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 May 2017
- Study start4 Jul 2017
- Primary completionAug 2018 (estimated)
- Study completionAug 2018 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Mild Haemophilia A Without InhibitorStudies of the same condition, open and under way.
- More trials run by The Hospital for Sick ChildrenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- The Hospital for Sick Children
- Sponsor type
- University, hospital or other
- Collaborators
- Canadian Hemophilia Society, Unity Health Toronto, Nationwide Children's Hospital
- Responsible party
- Principal investigator, Manuel Carcao, The Hospital for Sick Children
- Investigators
- Manuel Carcao, Principal investigator, Staff Haematologist
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03136003
- Sponsor's protocol ID
- 1000054948
- Status last verified
- Nov 2017
- First submitted
- 27 Apr 2017
- Last updated
- 4 Dec 2017
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: To ensure the safety of patients and to confirm the validity of our hypothesis, we plan to: * Meet after the first 10 patients have completed the study. * Analyze data from first 10 patients. This includes safety data as well as results of the blood tests including the standard hemostasis testing (FVIII;C, VWF:Ag, VWF:RCo, VWF:CBA, VWF:pp), and platelet function (PFA). * Determine whether there are measurable outcomes justifying further enrollment and DSMB will be able to make recommendations regarding terminating the study or amending the protocol if they deem that there are safety issues. * If any of the first 10 subjects develops any unexpected medical complication we will suspend recruitment pending re-evaluation of the study by the DSMB.
Study at a glance
From the registry record, last updated by the sponsor on 4 Dec 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- DDAVP vs Exercise in Patients With Mild Hemophilia A - Which is Better and do They Work Synergistically in Improving Hemostasis?
- ClinicalTrials.gov ID
- NCT03136003
- Acronym / sponsor ID
- 1000054948
- Conditions
- Mild Haemophilia A Without Inhibitor
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 30 participants (estimated)
- Lead sponsor
- The Hospital for Sick ChildrenUniversity, hospital or other
- Collaborators
- Canadian Hemophilia Society, Unity Health Toronto, Nationwide Children's Hospital
- Study start
- 4 Jul 2017 (actual)
- Primary completion
- Aug 2018 (estimated)
- Study completion
- Aug 2018 (estimated)
- First posted
- 2 May 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Individuals with mild hemophilia A (MHA) bleed infrequently but can in the setting of trauma which often is when participating in sports/exercise. Although both exercise and DDAVP (desmopressin) can raise Factor 8/Von Willebrand Factor (FVIII/VWF levels), it is not clear whether the pathophysiological mechanism is the same. Consequently it is not known if DDAVP and exercise would have additive effects in raising FVIII:C and VWF levels or if one would one negate the effect of the other. The aim of this 2 center (Sickkids and Columbus, Ohio), prospective, cross-over design study is to compare the impact of exercise vs. DDAVP on hemostasis in patients with MHA and also to investigate the impact of sequentially administering these interventions on their hemostatic indices.
Detailed description
Persons with mild hemophilia A (MHA) (defined as having a FVIII level of >5% to ≈40%) bleed infrequently but can in the setting of trauma which can often is in the context of participating in sports/exercise. FVIII levels temporarily rise with stress, exercise and with DDAVP (1-desamino-8-D-arginine vasopressin, desmopressin). In the case of DDAVP, the Hospital for Sick Children (SickKids) Hemophilia Team and others have shown that FVIII and VWF levels rise by 2-4 fold with DDAVP. Consequently many persons with MHA in an attempt to reduce their risk of bleeding take intranasal (IN) DDAVP prior to sports activities/exercise. IN DDAVP is reasonably expensive ($300/bottle of Octostim® in Canada and $700/bottle of Stimate® in USA), requires fluid restriction, and may be associated with nausea, vomiting, seizures and tachyphylaxis.
Recently, our group completed a pilot/feasibility study to evaluate the impact of a prescribed, moderate intensity aerobic exercise regimen on hemostatic indices in 30 children with hemophilia A [HA] or B [HB] (all severities) and documented a significant improvement in multiple coagulation parameters (platelet count, FVIII:C and von Willebrand factor [VWF]) with exercise. This improvement was particularly pronounced in 13 post-adolescent males with mild-moderate HA. In this sub-cohort, we noted a mean 2.3 fold increase in FVIII:C immediately after exercise, which remained significantly elevated at 1.9 fold,1 hour after completion of exercise
These changes in hemostatic variables associated with aerobic exercise may be protective against bleeding, and may negate the need to administer IN DDAVP immediately prior to sports participation.
Although both exercise and DDAVP can raise FVIII/VWF levels, it is not clear whether the pathophysiological mechanism in which they do this is the same. Consequently it is not known if DDAVP and exercise would augment each other's effects in raising FVIII:C and VWF levels or if one would one negate the effect of the other. Herein, we propose a prospective, interventional study of exercise vs IN DDAVP in 40-50 post adolescent (13-21 yr) males with MHA to compare their impact on hemostasis and also to investigate the impact of sequentially administering these interventions on hemostatic indices.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Arm A: DDAVP followed by exercise | Experimental | Drug: DDAVP, Behavioral: ExerciseIntervention #1: DDAVP. The participant will take either 1 or 2 nasal sprays of IN DDAVP. For patients weighing <50 kg: 150 ug (i.e. 1 spray into one nostril) and patients weighing ≥50 kg: 300 ug (i.e. 2 sprays - one into each nostril). Intervention #2: Exercise |
| Arm B: DDAVP alone | Active comparator | Drug: DDAVPIntervention #1: DDAVP. The participant will take either 1 or 2 nasal sprays of IN DDAVP. For patients weighing <50 kg: 150 ug (i.e. 1 spray into one nostril) and patients weighing ≥50 kg: 300 ug (i.e. 2 sprays - one into each nostril). Intervention #2: no further intervention (rest) |
| Arm C: Exercise alone | Experimental | Behavioral: ExerciseIntervention #1: Exercise Intervention #2: no further intervention (rest) |
| ARM D: Exercise followed by DDAVP | Experimental | Drug: DDAVP, Behavioral: ExerciseIntervention #1: Exercise Intervention #2: DDAVP. The participant will take either 1 or 2 nasal sprays of IN DDAVP. For patients weighing <50 kg: 150 ug (i.e. 1 spray into one nostril) and patients weighing ≥50 kg: 300 ug (i.e. 2 sprays - one into each nostril). |
Who may qualify
- Ages
- 13 to 21 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (2 listed)
- Patients ≥13 years of age and ≤21 years of age with Mild Hemophilia A (MHA), with a historical baseline FVIII:C level of ≥5% to ≤40% followed at either the Hospital for Sick Children or St. Michael's Hospital (Toronto).
- Patients ≥13 years of age and ≤21 years of age with genetically confirmed Mild Hemophilia A (MHA), with FVIII:C level of ≥5% to ≤50% followed at either the Hospital for Sick Children or St. Michael's Hospital (Toronto).
Key exclusion criteria (10 listed)
- A currently circulating or history of a previous inhibitor ( ≥0.5 BU) within the past 5 years. As inhibitor development in MHA is rare, it is not expected that any patient will be excluded for this reason.
- Any FVIII infusion or DDAVP use in the preceding week. This is to avoid an residual FVIII still being present in a patient who has taken an extended half-life FVIII.
- Co-existence of a congenital bleeding disorder other than MHA (e.g. VWD).
- Prior history of coronary artery disease or pulmonary disease, severe arthropathy interfering with ability to exercise.
- Patients on beta-blockers, anti-platelet agents or regular non-steroidal anti-inflammatory medications (e.g. Celebrex).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DDAVPAlso: IN DDAVP, OctostimThe participant will take either 1 or 2 nasal sprays of IN DDAVP (known as Octostim® in Canada). After receiving IN DDAVP, the participant will rest for 30 minutes. | Drug | ARM D: Exercise followed by DDAVP, Arm A: DDAVP followed by exercise, Arm B: DDAVP alone |
| ExerciseThe participant will exercise on a stationary cycle-ergometer using the previously-validated, progressively-incremental Godfrey protocol. Per the Godfrey protocol, the participant starts cycling on the calibrated cycle-ergometer with an initial exercise load dependent on their height. The workload is increased every minute in standard increments also based on the participant's height. All participants will exercise until they complete 3-minutes of cycling at 85% of their maximum predicted heart rate or exhaustion (whichever is first). Upon completion of planned exercise, work load is decreased to zero watts and participants will continue cycling at this cool-down rate for an additional 3-minutes, before getting off the ergometer. | Behavioural | ARM D: Exercise followed by DDAVP, Arm A: DDAVP followed by exercise, Arm C: Exercise alone |
Primary outcome
Factor 8 level after exercise
Time frame: Baseline, 30 min post intervention #1, 30 min post intervention#2 and 90 minute post intervention#2
To compare the increase in Factor 8 levels (FVIII:C) (measured as absolute and fold increase) associated with moderate intensity aerobic exercise (approximately 15 minutes of gradually increasing aerobic exercise culminating in 3-minutes of exercise at 85% of the predicted maximum heart rate) vs. IN DDAVP in post-adolescent males with MHA.
2 secondary outcomes
Factor 8 level after sequential administration of exercise followed by IN DDAVP (or vice versa)
Time frame: Baseline, 30 min post intervention #1, 30 min post intervention#2 and 90 minute post intervention#2
Associations between baseline physical activity scores and Factor 8 levels after exercise
Time frame: Baseline, 30 min post intervention #1, 30 min post intervention#2 and 90 minute post intervention#2
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Dec 2017.
- Individual participant dataSharing planned: Yes. To ensure the safety of patients and to confirm the validity of our hypothesis, we plan to: * Meet after the first 10 patients have completed the study. * Analyze data from first 10 patients. This includes safety data as well as results of the blood tests including the standard hemostasis testing (FVIII;C, VWF:Ag, VWF:RCo, VWF:CBA, VWF:pp), and platelet function (PFA). * Determine whether there are measurable outcomes justifying further enrollment and DSMB will be able to make recommendations regarding terminating the study or amending the protocol if they deem that there are safety issues. * If any of the first 10 subjects develops any unexpected medical complication we will suspend recruitment pending re-evaluation of the study by the DSMB.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Manuel Carcao principal investigator
Staff Haematologist
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing DDAVP and Exercise in people with Mild Haemophilia A Without Inhibitor, run by The Hospital for Sick Children at 2 sites in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 4 Dec 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Manuel Carcao (416-813-7654 ext. 205367, manuel.carcao@sickkids.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Factor 8 level after exercise (time frame: Baseline, 30 min post intervention #1, 30 min post intervention#2 and 90 minute post intervention#2). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Dec 2017.