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Contact Information.

Natasha Olby Vet MB,PhD, MRCVS, DACVIM (Neurology)
Phone: 919-513-8286
Email: natasha_olby@ncsu.edu

Kim Williams
Spinal Cord Injury Program Coordinator
Phone: 919-513-7235
Email: kimberly_williams@ncsu.edu

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Neurology

Clinical trials to evaluate and compare the effect of 4-Aminopyridine (4-AP) and T-BOC - a novel derivative of 4-AP - in dogs with chronic paraparesis

*Both of these trials have completed recruitment, data analysis is ongoing

 

Principal Investigator: Natasha Olby, Vet MB, PhD, DAVCIM
Study Coordinators: Ji-Hey Lim, DVM, PhD; Audrey Chanoit DVM, MS

Acute spinal cord injuries are a common problem in dogs, and due to the poor regenerative capacity of the nervous system, many dogs make an incomplete recovery and are left with permanent hind limb weakness. In spite of the lack of recovery, these dogs frequently have intact neural tissue at the level of the injury that has lost its ability to conduct messages due to loss of the normal insulating myelin sheath. Potassium channel antagonists block potassium channels on this exposed tissue, restoring its ability to conduct nerve impulses and improving function in the injured animal. Two potassium channel antagonists, 4-Aminopyridine (4-AP) and N- (4-pyridine) t-butyl carbamate derivative of 4-AP (T-BOC) will be evaluated in these trials.

4-AP has been shown to be effective at improving neurologic function following spinal cord injury in dogs and in humans with Multiple Sclerosis. However, its efficacy is limited and it can cause side effects such as anxiety, tremors, and even seizures.

T-BOC is novel potassium channel antagonist derived from 4-AP. It was developed by the Center for Paralysis Research at Purdue University, and preliminary testing at North Carolina State University College of Veterinary Medicine showed it to have an have an excellent safety profile; the clinically effective dose is 80 times lower than the toxic dose. It also appeared to be more effective than 4-AP at improving hind limb function in initial testing in dogs with spinal cord injuries.

We are running two clinical trials testing these drugs; the first trial will evaluate 4AP and TBOC in dogs that are paraplegic, and the second trial will evaluate TBOC in dogs with less severe spinal cord injuries. The details and inclusion criteria for each trial are listed below.

 

TBOC & 4AP

First Trial

Clinical trial to compare the effect of T-BOC, 4-AP and placebo on pelvic limb and bladder function in chronically paraparetic dogs

Sponsored by NeuroMetrix, Inc.

This blinded, prospective clinical trial will compare the effect of 4-AP, T-BOC, and placebo on hind limb and bladder function in chronically, severely paraparetic dogs.

Study hypothesis

N- (4-pyridyl) t-butyl carbamate derivative of 4-aminopyridine (4-AP) improves gait immediately and in the long term in dogs with chronic paraparesis and hind limb ataxia following acute spinal cord injury.

Inclusion Criteria  

  1. Dogs must have suffered a thoracolumbar spinal cord injury at least 6 months previously from which they have made an incomplete recovery.
  2. Dogs with only limited or no motor function in their hind limbs will be admitted. This will be determined at the first evaluation by the investigators.
  3. Dogs will have to be videotaped when walking on a treadmill and so we can only include dogs that will tolerate working with the investigators on the treadmill.
  4. Dogs must also be in good health other than their spinal cord injury; dogs with urinary tract infections will not be able to start the study until the infection is treated.
  5. The owner must be willing to come to the hospital with their dog once a week for the duration of the trial and fill out a short questionnaire in between weekly visits.

Study Protocol

Dogs will undergo an initial evaluation, dose titration and then a blinded 10-week trial period during which time they will receive both the drugs and the placebo at two-week intervals with a wash out period in the middle of the trial.

Phase 1: First appointment. Patients will be evaluated to determine whether they qualify for the study. This will involve reviewing their medical records and performing physical and neurological examinations. This first evaluation is at the owner’s expense.

Phase 2: Hospitalization for five days (for dose titration). Dogs that qualify for the study will be hospitalized at the Veterinary Health Complex for 5 days to determine the best dose of both T-BOC and 4-AP for each dog. Each day they will be given a different dose of one of the drugs to look for the dose that produces the maximum effect on their ability to walk. These doses will be the doses of drug that we will use in the trial over a 10-week period. If we see no response to either drug during this phase, they will not move into the last phase of the study.

Phase 3: Ten-week trial period. We will dispense a medication for the owner to give to their dog (by mouth) three times a day.

Patients will visit the Veterinary Health Complex once a week during this 10-week period to be evaluated when walking on a treadmill and outside with and without support. In addition, a neurological examination will be performed. Owners will be asked to fill out a short questionnaire on their dog’s progress each week.

Second Trial

Clinical trial to evaluate the Treatment of Chronic Paraparesis in Dogs using a Novel Derivative of 4-Aminopyridine

Sponsored by Morris Animal Foundation

Study hypothesis

N-(4-pyridyl) t-butyl carbamate derivative of 4-aminoryridine (4-AP) improves gait immediately and in the long term in dogs with chronic paraparesis and pelvic limb ataxia following acute spinal cord injury.

Inclusion Criteria

  1. Dogs must have suffered a severe thoracolumbar acute disc herniation at least 6 months prior to recruitment.
  2. Dogs must have severe, chronic gait deficits with a limited ability to bear weight, and have shown no clinical improvement over the previous month. The study investigators will confirm the recruitment during the first evaluation.
  3. Dogs will have to be videotaped when walking on a treadmill and we can only include dogs that will be comfortable working on the treadmill.
  4. Dogs must also be in good health other than their spinal cord injury; dogs with urinary tract infections will not be able to start the study until the infection is treated.
  5. The owner must be willing to come to the hospital with their dog once a week for the 12 week duration of the trial and fill out a short questionnaire in between weekly visits.

Study Protocol

20 dogs will be recruited in the study. They will be randomized in 2 groups: 10 dogs will be administered t-butyl derivative and 10 dogs will receive placebo. Dogs will be hospitalized for two days, and we will determine the most efficient dose of T-BOC for each dog.

Phase 1: Assessment of baseline function. Dogs will be evaluated at the Veterinary Health Complex once a week for the first month. At each of the 4 visits, they will undergo a neurological examination. Dogs will be walked outside on a non-slippery surface for a distance of about 20 feet, while we will videotape them from different angles and be walked on a treadmill for 5 -15 minutes in two to three short sections, again videotaping them. They won’t receive any medication at that point.

Phase 2:  Drug vs placebo administration period. During the next 4-week trial period, we will dispense a medication for the owner to give to their dog three times a day. The owners and investigators will be blinded on which drug each dog receives. The owners will be shown what exercise they can do at home every day and will be asked to complete a small questionnaire on how their dog is doing at home on a weekly basis. This will take approximately 5 to 10 minutes to complete. They will come to NCSU once a week over this 4 week period. At each of the 4 visits, dogs will undergo a neurological examination. They will be videotaped and their gait will be scored when walking on a treadmill and in the open field, same as performed in phase I. A blood sample will be obtained at each visit in order to measure plasma levels of the drug.

Phase 3: Washout period: comparison of the long-term outcome between the 2 groups. Following this period, the drug or placebo will be withdrawn and the weekly scoring assessments will continue for an additional month. 

dogs Tread mill training

 

Frequently Asked Questions

What are the benefits of enrolling my dog?
The biggest anticipated benefit is the possibility of either of the drugs improving your dog’s ability to walk; it is possible that 2 weeks of treatment might produce a permanent improvement. In addition, your dog will take part in a study that might identify an effective long-term treatment for paraparesis (hind limb weakness). This information will benefit future dogs with spinal cord injuries and the information generated may also be useful for treatment of people with spinal cord injuries. There is also some financial benefit. The study will supply the test drug at no cost to you, and all evaluations will be free of charge. In addition, a urine culture will be performed once a month at no cost to you. The cost of treating urinary tract infections will be your responsibility.

Are there any risks to my dog?
We are evaluating a novel drug that has been shown to have an excellent safety profile. However, whenever working with a relatively new drug, it is likely that all the potential side effects have not been identified. Your dog might have an unexpected reaction to the drug. 4-AP is known to cause tremors, anxiety and seizures when used at doses close to the therapeutic dose. In the first clinical trial, we will hospitalize your dog in the first 5 days to administer 4-AP at incremental doses to make sure that your dog can safely tolerate the dose we administer in the trial. If your dog does develop seizures from 4-AP, they are responsive to treatment with diazepam (valium).

If my dog shows a response to either drug, will they be available in the long term?
4-AP is available commercially in a form called Fampridine. T-BOC is not yet available commercially and we will keep owners informed of the evolving situation with this drug.

What are my responsibilities if I elect to enroll my dog in this study?
Owner responsibilities include:

  1. Administering the test drugs three times a day as prescribed.
  2. Coming to the hospital once a week with your dog for 10 to 12 weeks depending on the clinical trial your dog has been enrolled in.
  3. Completing a questionnaire every week during the study period.

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