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[2009-016442-74] Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells (MSCs) in multiple sclerosis.

Original authors : Llufriu S, Sepulveda M, Blanco Y, Marin P, Moreno B, et al.

Source : PLOS ONE | https://doi.org/10.1371/journal.pone.0113936

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Methods

Objective:

This randomized, double-blind, placebo-controlled, crossover phase II studies safety and efficacy of autologous mesenchymal stem cells in relapsing-remitting multiple sclerosis patients.

Assessment:

The study was performed in Hospital Clinic of Barcelona, Spain, between November 2010 and June 2012.
Nine patients unresponsive to conventional therapy, defined by at least 1 relapse and/or GEL on MRI scan in past 12 months, disease duration 2 to 10 years and Expanded Disability Status Scale (EDSS) 3.0-6.5, were randomized to receive IV 1-2E+6 bone-marrow-derives-MSCs/kg or Placebo.
After 6 months, the treatment was reversed and patients were followed-up for another 6 months.

Primary outcome criteria of this study is therefore the change number of gadolinium-enhancing lesions (GEL) on magnetic at the end of the study.
Secondary outcomes are (i) new lesions or enlarging lesions on serially registered long repetition time images, (ii) volume and percentage of brain volume change and (iii) clinical outcomes (relapses and disability by EDSS and MS Functional Composite).

Codings and variables generated following the freeze of the database
Original variable(s)	Created variable
Disease duration (DIFONSET_ENTRY)
Totalrelapses (TOTALRELAPSES)	Annualized relapse rate (ANNUALRELAPSES) resulting from an assignment (with DIFONSET_ENTRY TOTALRELAPSES)

EDSS_12m (EDSS_12M)
EDSS_6m (EDSS_6M)
EDSSbasal (EDSSBASAL)	EDSS change (EDSS) resulting from a listing (of EDSS_6M2 EDSS_12M2)

Flair_vol_12m (FLAIR_VOL_12M)
Flair_vol_6m (FLAIR_VOL_6M)
Flair_vol_bas (FLAIR_VOL_BAS)	Change in T2 lesion volume, ml (FLAIR_VOL) resulting from a listing (of FLAIR_VOL_6M2 FLAIR_VOL_12M2)

Flair_vol_bas (FLAIR_VOL_BAS)	T2 lesion volume, ml (FLAIR_VOL_BAS2) resulting from an assignment (with FLAIR_VOL_BAS)

Cumulative number of GEL (GAD_LESIONS_6M)
Cumulative number of GEL (GAD_LESIONS_E)
Number of GEL (GAD_LESIONS_BASAL)	Change in the number of GEL (GAD_LESIONS2) resulting from a listing (of GAD_LESIONS_6M2 GAD_LESIONS_E2)

N_T2_new_3m (N_T2_NEW_3M)
N_T2_new_6m (N_T2_NEW_6M)
N_T2_new_9m (N_T2_NEW_9M)
N_T2_new_D (N_T2_NEW_D)	Number of new or enlarging T2 lesions (N_T2_NEW2) resulting from a listing (of N_T2_NEW_6M2 N_T2_NEW_D2)

Prior approved disease-modifying therapy (FIRSTLINE) : – Betaferon – Ciclofosfamida – Copaxone – Rebif44	Prior approved disease-modifying therapy (RECOD_FIRSTLINE) resulting from a recoding : – 1 : Betaferon or ciclofosfamida – 2 : Copaxone – 3 : Rebif44

No of relapses (TOTALRELAP_1STINF)
No of relapses (TOTALRELAP_2NDINF)	No of relapses (TOTALRELAP) resulting from a listing (of TOTALRELAP_1STINF TOTALRELAP_2NDINF)

Grupo_tto (GRUPO_TTO)
REPETITIONS	Group (TRAIT1) resulting from a conditioning (on GRUPO_TTO REPETITIONS) : – MSCs – Placebo

Percentage of brain volume change, % (VOL_6MTO12M)
Percentage of brain volume change, % (VOL_BASELTO6M)	Percentage of brain volume change, % (VOL_BASELTO) resulting from a listing (of VOL_BASELTO6M VOL_6MTO12M)

MSFC, z score (ZMSFCS_BASAL)
ZMSFC_12m (ZMSFC_12M)
ZMSFC_6m (ZMSFC_6M)	MSFC z-score change (ZMSFC) resulting from a listing (of ZMSFC_6M2 ZMSFC_12M2)

Table 1 : Encodings

Study principles
Descriptions	Qualitative variables are described with frequencies and level percentages. Quantitative variables are described with means and standard deviations, quartiles, minimum/maximum.
Associations	The association between a quantitative parameter and « Group (TRAIT1) » item was evaluated with Student(Sd) test (paired samples), Wilcoxon(Wc) sign test or Friedman(Fm) test depending on the conditions of validity. The association between a qualitative parameter and « Group (TRAIT1) » item was evaluated with Mc Nemar(MN) test or Cochran(Cc) test.
Paired analysis	The association strength of the treatment with « Change in the number of GEL (GAD_LESIONS2) » item was evaluated and retranscribed as Mean differences with 95% confidence intervals and using Wald statistic.

Table 2 : Study principles

Flowchart

Figure 1 : Flowchart

Results : Initial characteristics

		Population		Group (TRAIT1)
		_		MSCs		Placebo
		N=18		N=9		N=9
		Mean±SD Med(Q1Q3) Min-Max or		Mean±SD Med(Q1Q3) Min-Max or		Mean±SD Med(Q1Q3) Min-Max or
Variable		n	%col	n	%col	n	%col
Gender (GENDER)	man	4	22.2	2	22.2	2	22.2
	woman	14	77.8	7	77.8	7	77.8
	Total	18	100	9	50	9	50

Age (AGE_ENTRY)	Mean ±SD	36.78	±8.17	36.78	±8.42	36.78	±8.42
	Median (Q1-Q3)	41	(30-43)	41	(30-43)	41	(30-43)
	Min-Max	23	48	23	48	23	48

Disease duration (DIFONSET_ENTRY)	Mean ±SD	8.26	±2.52	8.26	±2.59	8.26	±2.59
	Median (Q1-Q3)	9.08	(7.25-9.33)	9.08	(7.25-9.33)	9.08	(7.25-9.33)
	Min-Max	4.25	12.5	4.25	12.5	4.25	12.5

Relapses in previous 2 years (RELAPSES_2LASTY)	Mean ±SD	2.44	±1.29	2.44	±1.33	2.44	±1.33
	Median (Q1-Q3)	2	(2-3)	2	(2-3)	2	(2-3)
	Min-Max	1	5	1	5	1	5

Relapses in the last year (RELAPSE_LASTYEAR)	Mean ±SD	1.67	±0.84	1.67	±0.87	1.67	±0.87
	Median (Q1-Q3)	1	(1-2)	1	(1-2)	1	(1-2)
	Min-Max	1	3	1	3	1	3

Annualized relapse rate (ANNUALRELAPSES)	Mean ±SD	1.04	±0.49	1.04	±0.51	1.04	±0.51
	Median (Q1-Q3)	0.9	(0.63-1.52)	0.9	(0.63-1.52)	0.9	(0.63-1.52)
	Min-Max	0.55	1.84	0.55	1.84	0.55	1.84

EDSS (EDSSATENTRY)	Mean ±SD	4	±0.91	4	±0.94	4	±0.94
	Median (Q1-Q3)	3.5	(3.5-4)	3.5	(3.5-4)	3.5	(3.5-4)
	Min-Max	3	6	3	6	3	6

Time to EDSS 3.0 (years) (YEDSS3)	Mean ±SD	6.67	±1.99	6.67	±2.05	6.67	±2.05
	Median (Q1-Q3)	7	(5.5-7.5)	7	(5.5-7.5)	7	(5.5-7.5)
	Min-Max	3.8	10	3.8	10	3.8	10

Time to EDSS 4.0 (years) (YEDSS4)	Mean ±SD	7.27	±3.22	7.27	±3.48	7.27	±3.48
	Median (Q1-Q3)	6.67	(4.88-9.67)	6.67	(4.88-9.67)	6.67	(4.88-9.67)
	Min-Max	3.75	12	3.75	12	3.75	12

Time to EDSS 6.0 (years) (YEDSS6)	Mean ±SD	8	±0	8	±0	8	±0
	Median (Q1-Q3)	8	(8-8)	8	(8-8)	8	(8-8)
	Min-Max	8	8	8	8	8	8

MSFC, z score (ZMSFCS_BASAL)	Mean ±SD	-0.3	±0.51	-0.3	±0.52	-0.3	±0.52
	Median (Q1-Q3)	-0.28	(-0.76–0.09)	-0.28	(-0.76–0.09)	-0.28	(-0.76–0.09)
	Min-Max	-1.01	0.48	-1.01	0.48	-1.01	0.48

MSSS (MSSSENTRY)	Mean ±SD	5.82	±1.24	5.82	±1.28	5.82	±1.28
	Median (Q1-Q3)	5.36	(4.93-6.78)	5.36	(4.93-6.78)	5.36	(4.93-6.78)
	Min-Max	4.17	7.65	4.17	7.65	4.17	7.65

Number of GEL (GAD_LESIONS_BASAL)	Mean ±SD	4.67	±8.07	4.67	±8.32	4.67	±8.32
	Median (Q1-Q3)	0	(0-3)	0	(0-3)	0	(0-3)
	Min-Max	0	22	0	22	0	22

T2 lesion volume, ml (FLAIR_VOL_BAS2)	Mean ±SD	19.24	±15.74	19.24	±16.23	19.24	±16.23
	Median (Q1-Q3)	16.27	(12.84-20.83)	16.27	(12.84-20.83)	16.27	(12.84-20.83)
	Min-Max	3.08	58.17	3.08	58.17	3.08	58.17

Prior approved disease-modifying therapy (RECOD_FIRSTLINE)	Betaferon or ciclofosfamida	8	44.4	4	44.4	4	44.4
	Copaxone	4	22.2	2	22.2	2	22.2
	Rebif44	6	33.3	3	33.3	3	33.3
	Total	18	100	9	50	9	50

Table 3 : Initial characteristics cross sort

Results : Primary outcome

At the end of the study, no association is highlighted between Group and number of GEL (p = 0.0938 / p = 0.0612), number of new or enlarging T2 lesions (p = 0.5625), volume and percentage of brain volume change (p = 0.2031 / p = 0.2500) and clinical outcomes (p = 1.0000 / p = 0.8125 / p = 0.9453).
However, a trend to reduced mean GEL in patients treated with MSCs is observed.

		Population	Group (TRAIT1)
		_	MSCs	Placebo
		N=18	N=9	N=9	Statistic
Variable		Mean±SD Med(Q1Q3) Min-Max	Mean±SD Med(Q1Q3) Min-Max	Mean±SD Med(Q1Q3) Min-Max	p
Change in the number of GEL (GAD_LESIONS2)	Mean ±SD	0.11±6.22	-2.78±5.89	3±5.36	Wc p = 0.0938
	Median (Q1-Q3)	0(-1-2)	0(-5-0)	1(0-6)
	Min-Max	-16-15	-16-4	-3-15

Wc : Wilcoxon

Table 4 : Primary outcome cross sort

Figure 2 : Primary outcome

		Change in the number of GEL (GAD_LESIONS2)
		N=18	n=18
Variable		MD*[95%CI]	Wd p
Group (TRAIT1)	MSCs	0	0.0612
	Placebo	5.778[-0.345 ; 11.900]

Wd : Wald *MD : Mean Difference

Table 5 : Association strength of treatment with primary outcome

Results : Secondary outcomes

		Population	Group (TRAIT1)
		_	MSCs	Placebo
		N=18	N=9	N=9	Statistic
Variable		Mean±SD Med(Q1Q3) Min-Max	Mean±SD Med(Q1Q3) Min-Max	Mean±SD Med(Q1Q3) Min-Max	p
Number of new or enlarging T2 lesions (N_T2_NEW2)	Mean ±SD	23.39±40.47	23.78±42.42	23±40.99	Wc p = 0.5625
	Median (Q1-Q3)	9(0-21)	7(0-14)	12(0-21)
	Min-Max	0-130	0-130	0-130

Change in T2 lesion volume, ml (FLAIR_VOL)	Mean ±SD	1.73±3.2	0.58±1.17	2.89±4.16	Wc p = 0.2031
	Median (Q1-Q3)	0.78(0-1.88)	0.02(0-0.88)	1.08(0.09-2.96)
	Min-Max	-0.94-12.32	-0.94-3.18	-0.03-12.32

Percentage of brain volume change, % (VOL_BASELTO)	Mean ±SD	-0.35±0.46	-0.51±0.52	-0.19±0.34	Wc p = 0.2500
	Median (Q1-Q3)	-0.37(-0.59-0)	-0.5(-0.61–0.32)	-0.01(-0.5-0)
	Min-Max	-1.45-0.34	-1.45-0.34	-0.68-0.28

No of relapses (TOTALRELAP)	Mean ±SD	0.78±1.06	0.78±1.09	0.78±1.09	Wc p = 1.0000
	Median (Q1-Q3)	0(0-1)	0(0-1)	0(0-1)
	Min-Max	0-3	0-3	0-3

EDSS change (EDSS)	Mean ±SD	0.08±0.52	0.17±0.56	0±0.5	Wc p = 0.8125
	Median (Q1-Q3)	0(0-0)	0(0-0.5)	0(0-0)
	Min-Max	-1-1	-0.5-1	-1-1

MSFC z-score change (ZMSFC)	Mean ±SD	0.13±0.38	0.18±0.38	0.09±0.4	Wc p = 0.9453
	Median (Q1-Q3)	0.11(-0.15-0.31)	0.27(-0.15-0.29)	0(-0.04-0.31)
	Min-Max	-0.69-0.93	-0.25-0.93	-0.69-0.6

Wc : Wilcoxon

Table 6 : Secondary outcomes cross sort

Figure 3 : Secondary outcomes

Tables and figures

Table 1 : Encodings

Table 2 : Study principles

Table 3 : Initial characteristics cross sort

Table 4 : Primary outcome cross sort

Table 5 : Association strength of treatment with primary outcome

Table 6 : Secondary outcomes cross sort

Figure 1 : Flowchart

Figure 2 : Primary outcome

Figure 3 : Secondary outcomes

Date of completion : 2 August 2020

Implementer : RUS

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Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells (MSCs) in multiple sclerosis

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