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Exercise Versus DDAVP in Patients With Mild Hemophilia A

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ClinicalTrials.gov Identifier: NCT03379974
Recruitment Status : Active, not recruiting
First Posted : December 20, 2017
Last Update Posted : September 5, 2019
Sponsor:
Collaborator:
The Hospital for Sick Children
Information provided by (Responsible Party):
Riten Kumar, Nationwide Children's Hospital

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 Nationwide Children's), 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
Hemophilia A Drug: DDAVP Inhalant Product Behavioral: Exercise Intervention Phase 4

Detailed Description:

Persons with mild hemophilia A (MHA) (defined as having a FVIII level of >5% to ≈50%) 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-Darginine 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 Octistim® 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, the investigators 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, the investigators 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)
Actual Enrollment : 21 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: Exercise Versus DDAVP in Patients With Mild Hemophilia A - is One Non-inferior to the Other and do They Work Additively in Improving Hemostasis?
Actual Study Start Date : July 31, 2018
Actual Primary Completion Date : August 30, 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Experimental: ARM A: DDAVP followed by exercise
  1. Intervention #1: DDAVP Inhalant Product intervention 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).
  2. Intervention #2: Exercise intervention
Drug: DDAVP Inhalant Product
For the DDAVP intervention the participant will take either 1 or 2 nasal sprays of IN DDAVP. After receiving IN DDAVP, the participant will rest for 30 minutes.
Other Name: IN DDAVP

Behavioral: Exercise Intervention
For the exercise intervention 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 that is dependent on their height. The workload is increased every minute in standard increments also based on the participant's height. All participants will exercise till they complete 3-minutes of cycling at 85% of their maximum predicted heart rate or till exhaustion (whichever comes first). Upon completion of planned exercise, work load will be decreased to zero watts and participants will be instructed to continue cycling at this cool-down rate for additional 3-minutes, before getting of the ergometer.

Active Comparator: ARM B: DDAVP alone
  1. Intervention #1: DDAVP Inhalant Product intervention 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).
  2. Intervention #2: no further intervention (rest)
Drug: DDAVP Inhalant Product
For the DDAVP intervention the participant will take either 1 or 2 nasal sprays of IN DDAVP. After receiving IN DDAVP, the participant will rest for 30 minutes.
Other Name: IN DDAVP

Experimental: ARM C: Exercise intervention
  1. Intervention #1: Exercise intervention
  2. Intervention #2: no further intervention (rest)
Behavioral: Exercise Intervention
For the exercise intervention 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 that is dependent on their height. The workload is increased every minute in standard increments also based on the participant's height. All participants will exercise till they complete 3-minutes of cycling at 85% of their maximum predicted heart rate or till exhaustion (whichever comes first). Upon completion of planned exercise, work load will be decreased to zero watts and participants will be instructed to continue cycling at this cool-down rate for additional 3-minutes, before getting of the ergometer.

Experimental: ARM D: Exercise followed by DDAVP
  1. Intervention #1: Exercise intervention
  2. Intervention #2: DDAVP Inhalant Product intervention 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 Inhalant Product
For the DDAVP intervention the participant will take either 1 or 2 nasal sprays of IN DDAVP. After receiving IN DDAVP, the participant will rest for 30 minutes.
Other Name: IN DDAVP

Behavioral: Exercise Intervention
For the exercise intervention 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 that is dependent on their height. The workload is increased every minute in standard increments also based on the participant's height. All participants will exercise till they complete 3-minutes of cycling at 85% of their maximum predicted heart rate or till exhaustion (whichever comes first). Upon completion of planned exercise, work load will be decreased to zero watts and participants will be instructed to continue cycling at this cool-down rate for additional 3-minutes, before getting of 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 [ Time Frame: Baseline, 30 min post intervention #1, 30 min post intervention #2 and 90 minute post intervention #2 ]
    To compare the increase in FVIII:C (measured as absolute and fold increase) associated with a standardized moderate intensity aerobic exercise regimen (3-minutes of exercise at 85% of the predicted maximum heart rate) to intranasal 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 [ Time Frame: Baseline, 30 min post intervention #1, 30 min post intervention #2 and 90 minute post intervention ]
    To determine the absolute and fold increase in FVIII:C associated with the sequential administration of exercise followed by intranasal 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 [ Time Frame: Baseline, 30 min post intervention #1, 30 min post intervention #2 and 90 minute post intervention ]
    To explore the impact of baseline physical activity (measured using the International Physical Activity Questionnaire [IPAQ]-short form) on exercise induced increase in FVIII:C



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

Inclusion Criteria:

  • 1) Patients of ≥13 years of age and ≤21 years of age with MHA (FVIII:C level of ≥6% to ≤50%).

Exclusion Criteria:

  1. A currently circulating or a history of inhibitor (0.5 BU on two or more occasions). Inhibitor development is rare in MHA.
  2. History of FVIII infusion (both standard-acting and extended half-life products) or DDAVP use in preceding 1 week. Patients will be instructed to hold factor use or DDAVP for 1-week prior to participation in study, except for management of acute bleeds, in which case they will be instructed to inform the PI via telephone or e-mail.
  3. Patients with severe arthropathy (as determined by the principal investigator) interfering with ability to exercise. Severe arthropathy is rare in MHA.
  4. Patients on beta-blockers, anti-platelet agents or regular non-steroidal anti-inflammatory medications (e.g. Celebrex).
  5. Patients who are active smokers (cigarettes, marijuana).
  6. 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.
  7. Co-existence of a congenital bleeding disorder other than MHA (e.g. VWD).
  8. Patients with an active infectious or inflammatory condition. This includes previously identified HIV, active hepatitis B or C as reflected in elevated AST, ALT, RNA positivity for hepatitis B or C. HIV, hepatitis B and C are very rare in the age group (13-21 years) we hope to accrue in the proposed study.
  9. 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): NCT03379974


Locations
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United States, Indiana
Indiana Hemophilia and Thrombosis Center
Indianapolis, Indiana, United States, 46260
United States, Ohio
Akron Children's Hospital
Akron, Ohio, United States, 44308
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
Dayton Children's Hospital
Dayton, Ohio, United States, 45404
Sponsors and Collaborators
Nationwide Children's Hospital
The Hospital for Sick Children
Investigators
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Principal Investigator: Riten Kumar, MD, MSc Nationwide Children's Hospital

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Responsible Party: Riten Kumar, Prinicipal Investigator, Nationwide Children's Hospital
ClinicalTrials.gov Identifier: NCT03379974     History of Changes
Other Study ID Numbers: IRB17-00290
First Posted: December 20, 2017    Key Record Dates
Last Update Posted: September 5, 2019
Last Verified: September 2019
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), platelet function (PFA), Thromboelastography (TEG) and Thrombin generation.
  • 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: Yes
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