Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT03367429 |
| Other study ID # |
1708018456 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
June 15, 2018 |
| Est. completion date |
September 18, 2019 |
Study information
| Verified date |
November 2021 |
| Source |
Weill Medical College of Cornell University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Despite the wide-spread use of botulinum toxin (BT) to treat spasticity (increased muscle
tone) in central neurological disease, evidence-based guidance on dosing, dilution, and
injection technique is limited. The wide-spread use of BT in spasticity management, expense
of these agents, and detrimental impact from movement into non-injected muscles mandates a
better understanding of BT movement within muscles. A proof-of-concept paper written by
investigators at Weill Cornell Medicine introduced a non-invasive MRI approach with "voxel
thresholds" that was able to detect intramuscular effects of BT at 2 and 3 months
post-injection of BT. The purpose of the current set of studies is to refine this MRI
technique to better visualize the movement of botulinum toxin through muscle. In addition,
the investigators plan to explore, using the imaging technique, how spastic muscle and
differing dilutions affect BT movement in an effort to support the development of better
research techniques to study toxin movement in human muscle.
Description:
The research questions for the present study series are as followed:
1. How does the movement and morphology of BT muscle effect (BTME) differ between
standardized, research injections into spastic and non-spastic lateral gastrocnemius
muscle (LGM)?
2. How does the movement and morphology of BTME differ between a standardized, research
injection into spastic LGM versus an injection using the same dose in a 100% greater
dilution?
3. Is there a predictable BTME within a given muscle following lower extremity BT clinical
injections based on clinical need?
The two hypotheses are as followed:
First, it is predicted that BT muscle effect (BTME) will be greater in normal muscle than in
spastic muscle.
Second, it is predicted that BTME will increase with increasing dilution.
The standard BT injection will be an injection of 25 units of onobotulinumtoxinA (Botox®)
diluted in 0.25cc of saline.
The experimental BT injection will be an injection of 25 units of onobutilinumtoxinA (Botox®)
diluted in 0.50cc of saline.
The clinical BT injection will be an injection of up to 200 units of onobutilinumtoxinA
(Botox®) to any clinically indicated muscle or combinations of muscle in the spastic leg.
Dose, dilution, and site of injection will be determined by the PI and all parameters of each
injection tracked for future reference.
At baseline, subjects will receive research injections that are decided based on the research
protocol. Given the very small dosage of the research BT injections, the investigators do not
anticipate seeing any symptomatic effects in subjects. At 3 months following research
injections, subjects will receive clinical injections that are decided based on their
clinical need and are anticipated to result in clinical benefit for subjects. All subjects
will have an MRI at baseline (MRIB), at 2M (months) following research injections (MRI2), and
at 2M following clinical injections (MRI3).
Experiment #1 - Pilot:
The pilot experiment will be done to inform the study design for the subsequent experiments.
For the pilot experiment, after a baseline MRI, 6 subjects will be randomized into three
groups (N=2 in each group): standard injection in LGM, experimental injection in LGM, or
experimental injection in medial gastrocnemius muscle (MGM). All 6 subjects will receive a
standard injection to the non-spastic LGM. Subjects will undergo a second MRI 2 months after
the research injections, which will be used to confirm the design of the subsequent
experiments.
If, for the data from the investigator's pilot study of N=6 subjects, the investigators find
on MRI2 a similar appearance and volume of BTME (BTME volume +/- 20%) for both the LGM and
MGM receiving the experimental injection and that the BTME is contained within each muscle,
the investigators will have the option of proceeding with the within-subject design where
each subject serves as his or her own control, receiving either the research or experimental
injection in the spastic LGM and the alternative injection in the spastic MGM. If the
within-subject design is used, 15 subjects will be recruited. If the BTME volumes for the LGM
and MGM receiving the experimental injection are not within +/- 20% of each other, or the
investigators see on the MRI that the BTME is not contained within each injected muscle, then
a between subject design will be used where subjects will be randomized to receive either the
experimental or standard injection to the spastic LGM and 25 subjects will be recruited.
Subjects will receive clinical injections 3 months following the research injections and
undergo a final MRI 2 months following clinical injections. Recruitment for the subsequent
experiments will begin after data analysis from the second MRI in experiment #1 is complete.
Experiment #2 (Effect of dilution, answer Research Question #1):
If using a within-subject design, subjects will be randomized to receive a standard injection
to either the LGM or MGM. The experimental injection will be delivered to the muscle not
receiving the standard injection. If using a between-subjects design, subjects will be
randomized to receive either a standardized injection in the LGM or an experimental injection
in the LGM. On the same day of, but before the injection, the MRIB will be acquired. Using
the localization schema proposed in the investigator's proof-of-concept study, the baseline
scan will be used to determine the coordinates and depth of the injection into a given
muscle. Two months (+/- 1 week) after the injection, subject will report for MRI2 and will be
considered finished with Experiment #2. He/she will be scheduled for the "clinical" injection
5 weeks (+/- 1 week) from that time, which will be evaluated in Experiment #4.
Experiment #3 (spastic vs. non spastic muscle, answer Research Question #2):
Experiment #3 will take place simultaneously and within the same subject population as
Experiment #2. Regardless of whether a within- or between subject design is adopted in
Experiment #2, all subjects will also receive a standard injection to the non-spastic LGM.
The same technique using MRIB for muscle localization and the same protocol for obtaining
MRI2 employed in Experiment #2 will be used for Experiment #3, at the same time points.
Subjects will be scheduled for the "clinical" injection 5 weeks (+/- 1 week) from the time of
MRI2, as mentioned under the description for Experiment #2.
Experiment #4:
As described previously, all subjects that participated in Experiments #2 and #3 will undergo
a cycle of clinically-based BT injections to the spastic lower extremity no sooner than 3
months after the research injections and about 1 month after MRI2. Potentially, any lower
extremity muscle or combination of muscles may be injected based on clinical evaluation and
need. The investigators reserve the right to limit the total dose of toxin injected to no
more than 200 units of onobotulinumtoxinA. This would be a reasonable dose in clinical
practice for the first cycle of lower extremity injections in a toxin-naive patient. All
subjects will receive a third and final leg MRI3 2 months following the clinical injection,
marking the end of this study approximately 5 months after the initial randomization in
Experiment #2.
