WU HSIEN-MING (TW)
DOONG HOWARD (TW)
JIANG TSUNG-SHANN (TW)
KING CHI HSIN RICHARD (US)
CN103877376B | 2016-09-14 | |||
US7223425B2 | 2007-05-29 | |||
JP4109907B2 | 2008-07-02 |
DO BRYAN: "Top 4 Supplement Additives You Should Know About", DRFORMULAS, 1 December 2018 (2018-12-01), XP055901131, Retrieved from the Internet
MAYO CLINIC STAFF: "Depression (major depressive disorder)", MAYO CLINIC, 3 February 2018 (2018-02-03), XP055901132, Retrieved from the Internet
W HAT IS CLAIMED IS : 1. A method of treating major depressive disorder (MDD) comprising orally administering to a subject in need thereof a composition containing an amount of a botanical extraction at daily dose of 380 - 3800 mg; wherein the botanical extraction is one or a combination of: i) a polar solvent extract from the dry root of Polygala tenuifolia Willd, the polar solvent being water or a mixture of water and methanol or ethanol; ii) an aqueous fraction resulting from an extraction of the polar solvent extract with an organic solvent; iii) an organic eluent by introducing the polar solvent extract or the aqueous fraction into a reverse phase chromatography column, and eluting the column with water and an organic solvent; and iv) a filtrate having a molecular mass less than 30,000 in the organic eluent. 2. The method of claim 1, wherein the composition is administered in an oral dosage form. 3. The method of claim 1, wherein the composition further contains silicon dioxide and magnesium stearate and is in the form of a capsule. 4. The method of claim 3, wherein the composition is administered at the onset of an episode of a symptom of the depressive disorder. 5. The method of claim 3, wherein the composition is administered chronically. 6. The method of claim 5, wherein the composition is administered on a schedule throughout the day. 7. The method of claim 6, wherein the said daily dose is administered once per day, twice per day, or three times per day. 8. The method of claim 7, wherein each dose is 380 - 760 mg of the botanical extraction. 9. The method of claim 8, wherein the administration is daily over at least 25 days. 10. The method of claim 5, wherein the said subject is under evaluation at the end of administration and after at least one month thereafter. 11. The method of claim 10, wherein the said evaluation comprises administering and evaluating the results of the Montgomery-Asberg Depression Rating Scale (MADRS) and/or the Hamilton Depression Rating Scale (HAM-D-17) and/or the Hamilton Anxiety Rating Scale (HAM-A) and/or the Clinical Global Impression Scale (CGI), and/or the Columbia-Suicide Severity Rating Scale (C-SSRS ). |
Table 3. Frequencies of Adverse Events [0034] In summary, no subject had serious adverse event and no subject discontinued due to adverse event. No clinically significant findings in physical examinations, vital signs, electrocardiogram, laboratory measurements, and C-SSRS was observed throughout the treatment period. The oral administration of PDC-1421 in healthy volunteers was safe and well-tolerated for the dose from 380 mg to 3800 mg. [0035] Example 6: Phase II in major depressive disorder (MDD) patients [0036] This Phase II clinical trial was aimed to evaluate the safety and efficacy of PDC-1421 in adults with MDD. This study included two parts. The Part I study was a multiple center, open label, dose escalation evaluation with two dosage levels (1 or 2 capsules TID; 1140 mg or 2280 mg per day) sequentially. The Part II study was a multiple center, randomized (1:1:1), double-blind, placebo-controlled, parallel groups with three study arms to compare efficacy and safety profiles of PDC-1421 Capsule at two dosage levels (either 1 or 2 capsules TID) versus control (placebo TID). [0037] The primary objective was to assess the efficacy profile of PDC-1421 Capsule in major depressive disorder (MDD) with Montgomery-Åsberg Depression Rating Scale (MADRS). The secondary objective was to evaluate the efficacy and safety profile of PDC-1421 Capsule in MDD with other rating scales. [0038] In Part I, 12 subjects were randomized to Cohort 1 (low-dose group, N=6) and Cohort 2 (high-dose group, N=6). All subjects completed the study, and no subject withdrew from Part I. In Part II, 60 subjects (50 at Taiwan sites and 10 at United State site) were randomized to 3 study arms: (1) Low-dose group (N=19), (2) High-dose group (N=19) and (3) Placebo group (N=20). A total of 48 subjects completed and 12 subjects withdrew from the study (Low-dose group: N=5; High-dose group: N=2; Placebo group: N=5). [0039] Efficacy results [0040] In the ITT population, net changes in MADRS from baseline to Week 6 were -9.21, -13.19, and -9.20 for Low-dose group, High-dose group and Placebo group, respectively. In the PP population, net changes in MADRS from baseline to Week 6 were - 10.40, -13.40, and -8.64 for three treatment arms respectively. The greater reduction in mean score of MADRS was observed in the High-dose group compared to Low-dose group and Placebo group in both ITT and PP populations, but the group difference did not reach statistical significance. [0041] The net changes in MADRS, HAM-D-17, HAM-A, DSSS-depression, and CGI-severity and response rates in MADRS and HAM-D-17 at Week 6 in ITT population were summarized in the below table 4.
Table 4. The efficacy results at Week 6 in ITT population 1: Kruskal-Wallis test 2: Cochran-Mantel-Haenszel test [0042] In the ITT population the net changes in HAM-D-17 from baseline to Week 6 were -8.8, -11.0, and -8.7 for Low-dose group, High-dose group and Placebo group, respectively. In the PP population, net changes in HAM-D-17 from baseline to Week 6 were - 10.0, -11.1, and -7.9 for three treatment arms, respectively. The greater reduction in mean score of HAM-D-17 was observed in the High-dose group compared to Low-dose group and Placebo group in both ITT and PP populations, but the group difference did not reach statistical significance (P=0.406 for ITT; P=0.392 for PP). [0043] A significant group difference on net change in HAM-D-17 and HAM-A in ITT population at Week 2 was found between three groups (P=0.038 for HAM-D-17; P=0.041 for HAM-A). Post-hoc pair-wise comparisons demonstrated a significant difference between High-dose group and Placebo group in HAM-D-17 (High-dose vs. Placebo = -7.90 vs. -4.30; Adjusted P=0.039) and HAM-A (-5.38 vs. -2.90, Adjusted P=0.022), but not for Low- dose group versus Placebo, suggesting that subjects who took 2 PDC-1421 Capsules TID showed greater improvement compared with those in the Placebo group by Week 2 (net change=3.6 for HAM-D-17; 2.48 for HAM-A). [0044] At Week 6, for MADRS, no significant group difference was observed in response rate in ITT population (P=0.230) and a nearly significant difference in PP population (P=0.062). Percentage of “responders” at Week 6 was highest in High-dose group (Low-dose vs. High-dose vs. Placebo = 32% [n=6] vs.52% [n=11] vs.35% [n=7] in ITT population; 33% [n=5] vs.53% [n=8] vs. 29% [n=4] in PP population). [0045] At Week 2, for HAM-D-17, a significant group difference was found between three treatment groups in both ITT and PP population (P=0.028 and 0.037, respectively). Percentages of “responders” were highest in the Low-dose group, followed by High-dose and Placebo groups in ITT and PP populations (Low-dose vs. High-dose vs. Placebo=26% vs. 14% vs. 10% in ITT; 27% vs.20% vs. 14% in PP). [0046] Safety results [0047] The safety evaluation was based on the ITT population, who took at least one dose of the IPs and had any of the post-baseline safety data collected. [0048] Regarding the incidence of TEAEs, a total 4 subjects (33.3%) experienced at least one TEAE with 2 subjects in each dose cohort in Part I study; a total of 32 subjects (53.3%) experienced at least one TEAE with 12 (63.2%) in the Low-dose group, 11 (52.4%) in the High-dose group, and 9 (45.0%) in the Placebo group for Part II study. [0049] For more common TEAEs, the most frequently reported TEAEs in Part I included “Infections and infestations” (Total: n=2 [16.7%]; Low-dose: n=1; High-dose: n=1) and “Psychiatric disorders” (Total: n=2 [16.7%]; Low-dose: n=0; High-dose: n=2). in Part H, the most commonly reported TEAEs included “Gastrointestinal disorders” (Total: n=17
[28.3%], Low-dose: n=7; High-dose: n=5; Placebo: n=5), “Nervous system disorders” (Total: n=4 [6.7%]; Low-dose: n=1 ; High-dose: n=2; Placebo: n=1) and “Psychiatric disorders” (Total: n=4 [6.7%]; Low-dose: n=3; High-dose: n=0; Placebo: n=1). Among TEAEs with incidence
>5%, more subjects reported “Dry mouth” in both Low-dose and High-dose treatment groups
(n.=3 for each group) than those in the Placebo group (n=1).
[00.50] For level of severity, a total of 6 TEAEs were rated as mild or moderate in
Part I study; a total of 68 TEAEs were recorded in Part. IT study (No. of events: Low-dose group vs. High-dose group vs. Placebo group=20 vs. 26 vs. 22), with 53 events rated as mild (19 vs.
17 vs. 17), 14 events as moderate (1 vs. 9 vs. 4) and 1 event rated as severe in Placebo group.
No deaths or SAEs occurred in this study.
[0051] For occurrence of AE in the withdrawals, two withdrawn subjects (Low- dose group: n=1; Placebo group: n=1) were due to depression, and one subject (Low-dose group) was due to anxiety and this event was judged to be unlikely related to the test product by the PI. These AEs might be condition related, but not treatment related.
[00.52] Regarding the laboratory values at each scheduled visit, few abnormal values with clinical significance (CS) were observed in either Part 1 or Part II study. The highest incidence of abnormalities with CS was on triglyceride (Part 1: n=1 in High-dose group: Part
II: n=3 in High-dose group).
[0053] For vital signs and ECG, no subject was evaluated as abnormalities with
CS in Part I study. For Part II study, abnormal SBP and DBP with CS were detected in the
High-dose group (SBP at Week 4 and Week 6: n=1 : DBP from baseline to Week 7 : n=1). All of these abnormal blood pressure events were detected in the same subject with a hypertension medical history. All other values were evaluated as norma! or abnormal with non-clinical significance (NCS), without changing to abnormality with CS for either vital signs or ECG. [0054] For physical examination, no subject was changed from normal to abnormal (NCS or CS) for all the scheduled visits in both Part I and Part II studies, suggesting that no physical evaluation became worse during treatment and follow-up period. [0055] With regard to the assessment of suicidal ideation and behavior, incidence of ‘suicidal ideation’ and ‘suicidal ideation or suicidal behavior’ based on C-SSRS were low and similar between two groups in the Part I study with around 1 to 2 subjects; no ‘suicidal behavior’ was observed during treatment. For Part II, ‘suicidal behavior’ was not observed in any of the three groups. These results suggest that treatment of PDC-1421 did not increase the risk of either suicidal ideation or suicidal behavior. [0056] From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the scope of the following claims.
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