Brief Title
Exercise Versus DDAVP in Patients With Mild Hemophilia A
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?
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.
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.
Study Phase
Phase 4
Study Type
Interventional
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
Secondary Outcome
•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
Condition
Hemophilia A
Intervention
DDAVP Inhalant Product
Study Arms / Comparison Groups
ARM A: DDAVP followed by exercise
Description: 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). Intervention #2: Exercise intervention
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
32
Start Date
July 31, 2018
Completion Date
December 5, 2019
Primary Completion Date
August 30, 2019
Eligibility 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).
Gender
Male
Ages
13 Years - 21 Years
Accepts Healthy Volunteers
No
Contacts
Riten Kumar, MD, MSc, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT03379974
Organization ID
IRB17-00290
Responsible Party
Sponsor
Study Sponsor
Nationwide Children's Hospital
Collaborators
The Hospital for Sick Children
Study Sponsor
Riten Kumar, MD, MSc, Principal Investigator, Nationwide Children's Hospital
Verification Date
February 2020