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DDAVP vs. Exercise in Patients With Mild Hemophilia A

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ClinicalTrials.gov Identifier: NCT03136003
Recruitment Status : Recruiting
First Posted : May 2, 2017
Last Update Posted : December 4, 2017
Sponsor:
Collaborators:
Canadian Hemophilia Society
St. Michael's Hospital, Toronto
Nationwide Children's Hospital
Information provided by (Responsible Party):
Manuel Carcao, The Hospital for Sick Children

Brief 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 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.

Condition or disease Intervention/treatment Phase
Mild Haemophilia A Without Inhibitor Drug: DDAVP Behavioral: Exercise Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Masking Description: The randomization of the participant to a study arm will be done prior to the study visit by the pharmacy at the hospital. The Investigator and study team will know the arm each participant is in before the patient's visit. This information will also be provided to the participant before the visit.
Primary Purpose: Treatment
Official Title: DDAVP vs Exercise in Patients With Mild Hemophilia A - Which is Better and do They Work Synergistically in Improving Hemostasis?
Actual Study Start Date : July 4, 2017
Estimated Primary Completion Date : August 2018
Estimated Study Completion Date : August 2018


Arm Intervention/treatment
Experimental: Arm A: DDAVP followed by exercise

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

Drug: DDAVP
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.
Other Name: IN DDAVP, Octostim

Behavioral: Exercise
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.

Active Comparator: Arm B: DDAVP alone

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)

Drug: DDAVP
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.
Other Name: IN DDAVP, Octostim

Experimental: Arm C: Exercise alone

Intervention #1: Exercise

Intervention #2: no further intervention (rest)

Behavioral: Exercise
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.

Experimental: ARM D: Exercise followed by DDAVP

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).

Drug: DDAVP
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.
Other Name: IN DDAVP, Octostim

Behavioral: Exercise
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.




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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 ]
    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).

  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 ]
    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).



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Ages Eligible for Study:   13 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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).

Exclusion Criteria:

  • 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.
  • 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03136003


Contacts
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Contact: Manuel Carcao 416-813-7654 ext 205367 manuel.carcao@sickkids.ca
Contact: Patrick Ng 416-813-2145 ext 302145 patrick.ng@sickkids.ca

Locations
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Canada, Ontario
St. Michael's Hospital Not yet recruiting
Toronto, Ontario, Canada, M5B 1W8
Contact: Michelle Sholzberg         
Sub-Investigator: Michelle Sholzberg         
The Hospital for Sick Children Recruiting
Toronto, Ontario, Canada, M5G1X8
Contact: Manuel Carcao         
Contact: Patrick Ng         
Principal Investigator: Manuel Carcao         
Sponsors and Collaborators
The Hospital for Sick Children
Canadian Hemophilia Society
St. Michael's Hospital, Toronto
Nationwide Children's Hospital
Investigators
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Principal Investigator: Manuel Carcao Staff Haematologist

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Responsible Party: Manuel Carcao, Hematologist, The Hospital for Sick Children
ClinicalTrials.gov Identifier: NCT03136003     History of Changes
Other Study ID Numbers: 1000054948
First Posted: May 2, 2017    Key Record Dates
Last Update Posted: December 4, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

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.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Deamino Arginine Vasopressin
Factor VIII
Coagulants
Hemostatics
Antidiuretic Agents
Natriuretic Agents
Physiological Effects of Drugs