Exercise Versus DDAVP in Patients With Mild Hemophilia A

NCT ID: NCT03379974

Last Updated: 2020-02-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-07-31
• Study Completion Date: 2019-12-05

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.

Conditions

Hemophilia A

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

DDAVP Inhalant Product

Intervention Type: DRUG

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.

Exercise Intervention

Intervention Type: BEHAVIORAL

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.

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)

Group Type: ACTIVE_COMPARATOR

DDAVP Inhalant Product

Intervention Type: DRUG

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.

ARM C: Exercise intervention

1. Intervention #1: Exercise intervention

2. Intervention #2: no further intervention (rest)

Group Type: EXPERIMENTAL

Exercise Intervention

Intervention Type: BEHAVIORAL

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.

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).

Group Type: EXPERIMENTAL

DDAVP Inhalant Product

Intervention Type: DRUG

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.

Exercise Intervention

Intervention Type: BEHAVIORAL

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.

Interventions

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.

Intervention Type: DRUG

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.

Intervention Type: BEHAVIORAL

Other Intervention Names

IN DDAVP

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).

• Minimum Eligible Age: 13 Years
• Maximum Eligible Age: 21 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

The Hospital for Sick Children

OTHER

Sponsor Role: collaborator

Nationwide Children's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Riten Kumar, MD, MSc

Role: PRINCIPAL_INVESTIGATOR

Nationwide Children's Hospital

Locations

Indiana Hemophilia and Thrombosis Center

Indianapolis, Indiana, United States

Akron Children's Hospital

Akron, Ohio, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

Dayton Children's Hospital

Dayton, Ohio, United States

Countries

United States

Other Identifiers

IRB17-00290

Identifier Type: -

Identifier Source: org_study_id